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cle autoantibodies (ASMA); however, the nature of this association remains controversial.

A diagnosis of NAFLD is made when all the following

conditions are met:

• Evidence of steatosis on liver biopsy or imaging

• Exclusion of chronic alcohol abuse

• Exclusion of other causes of steatosis

• Absence of concomitant chronic liver disease.

Most often, imaging, along with a detailed history, is sufcient to diagnoseNAFLD.Although not recommended for most patients, biopsy examination is indicated in doubtful cases or to determine the degree of hepatocellular injury. In addition, liver biopsy is currently the only diagnostic tool to differentiate NAFLD from NASH.Although often altered in patients with NAFLD, laboratory tests are not useful for diagnostic purposes but are essential to evaluate other conditions in the differential diagnosis. To this end, serologic tests for HCV, HAV, and HBV infection should be performed, and other chronic liver diseases, such as autoimmune hepatitis and hemochromatosis, should be excluded (Table11.12).

Based on the patient’s symptomatology and personal and family history, Wilson’s disease, hypo- or hyperthyroidism, celiac disease, α1-antitrypsin deciency, HELLP syndrome during pregnancy, and Budd–Chiari syndrome should be ruled out.

Radiological diagnosis usually requires an abdominal ultrasound. Although steatosis can also be detected by computed tomography or magnetic resonance imaging, none of these investigations allows differentiation of NAFL from NASH. The radiographic diagnosis should include radiographic ndings of fatty liver inltration, exclusion of other causes of steatosis, absence of signs or symptoms of cirrhosis, and low risk of advanced brosis. If these criteria are not met, a liver biopsy should be performed for diagnostic conrmation and to ascertain the degree of severity of the disease.

Regarding the opportunity to screen individuals at risk of NAFLD, such as obese or diabetic individuals, several scientic societies, such as the American Association for the Study of Liver Diseases, have expressed some skepticism toward this approach, given the uncertainty regarding which diagnostic tests to use and how to treat affected individuals.

Table 11.12 Main laboratory tests for the differential diagnosis of NAFLD

Anti-HCV antibodies Anti-HAV antibodies (IgG) HBsAg, HBeAg Sideremia, ferritin, transferrin saturation ANA, ASMA, anti-LKM-1

ANA anti-nuclear antibodies, anti-LKM-1 anti-liver microsome type 1 antibodies, ASMA anti-smooth muscle antibodies, HBeAg hepatitis B antigen E, HBsAg hepatitis B surface antigen

Alcoholic Hepatopathy

Chronic alcohol abuse is associated with variousliver manifestations, including steatosis (with or without steatohepatitis), alcoholic hepatitis, cirrhosis, and hepatocarcinoma. Chronic alcohol abuse is dened by an intake >210g/week in men or >140g/week in women over at least 2years, with particular attention to weekly and daily intake patterns. Alcohol abuse is widespread worldwide. A prevalence of 18% in the adult population in the United States has been documented.

Hepatic steatosis is present in 90% of subjects who abuse alcohol and is typically macrovesicular. It can occur as early as after a couple of weeks of regular alcohol ingestion and can resolve spontaneously by abstaining from alcohol. Approximately one-third of patients with steatosis develop liver inammation (steatohepatitis) if alcohol intake continues over time. In about 10% of patients, steatosis progresses to cirrhosis. Steatohepatitis represents a condition with a higher risk of cirrhosis than steatosis alone.

The clinical manifestations of alcoholic hepatopathy vary depending on the severity of the liver injury. On physical examination,patients with steatosis alone are almost always asymptomatic and often present with hepatomegaly on physical examination. Patients with alcoholic hepatitis typically present with jaundice. Alcoholic cirrhosis is associated with jaundice, asthenia, peripheral edema, symptoms of gastrointestinal bleeding, palmar erythema, ascites, and confusional states of hepatic encephalopathy of the more advanced forms characterized by hepatic insufciency.

From a clinical biochemistry point of view, patients with alcoholic hepatopathy present various alterations in the haematochemical picture, although none of them is diagnostic. The classic picture includes an increase in serum transaminases, with an AST/ALT ratio >1, often even >2, unlike what happens in other forms of hepatopathy in which the most marked increase is in ALT compared to AST, and therefore, the AST/ALT ratio remains below 1. The increase in AST is usually over eight times the upper reference limit, while that in ALT usually does not exceed ve times the upper reference limit. The fact that the relative increase in ALT is smaller than that of AST has been attributed, at least in part, to the deciency of pyridoxal-phosphate, a cofactor of ALT.According to this hypothesis, the altered AST/ALT ratio would reect an inappropriate increase in ALT rather than a disproportionate increase in AST.

The extent of the increase in transaminases does not reect the degree of severity of the liver disease. Normal or only moderately elevated transaminases are not uncommon.

An AST/ALT ratio >1 may be observed in patients with steatohepatitis and, more frequently, in patients with nonalcoholic cirrhosis. However, if the AST/ALT ratio is >2, the

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etiology will be alcoholic since such values are very rarely seen in other forms of hepatopathy.

Serum γ-glutamyltransferase (GGT) is often increased in alcoholic liver disease and remains so even after several weeks of abstinence from alcohol intake. GGT is not specic for alcoholic liver disease because it may be increased in all forms of cholestatic jaundice or following the intake of certain drugs, such as barbiturates or phenytoin.

Increased total bilirubin is common in decompensated cirrhosis, regardless of the cause.

Cirrhotic or malnourished patients have hypoalbuminemia.

Haematological abnormalities in patients with alcoholic hepatopathy include thrombocytopenia, anaemia, increased mean corpuscular volume (MCV), neutropenia, increased erythrocyte sedimentation rate (ESR), and prolonged INR (International Normalized Ratio). Macrocytosis is an expression of disease that persists over time and results from folate and vitamin B12 deciency, direct alcohol toxicity, and lipid accumulation in the erythrocyte membranes. Thrombocytopenia may result from primary bone marrow hypoplasia or splenic sequestration caused by portal hypertension and splenomegaly.

In patients in whom cirrhosis is accompanied by hepatorenal syndrome, hyponatremia, and increased serum creatinine may also be observed.

Alcoholic hepatopathy is diagnosed based on a compatible clinical history, nding of hypertransaminasemia, hepatic steatosis on the radiographic investigation, or liver biopsy. It is a diagnosis of exclusion from other causes of hepatic steatosis listed in Table11.11.

The differential diagnosis of alcoholic hepatopathy should include chronic viral hepatitis, hemochromatosis, primary biliary cirrhosis, primary sclerosing cholangitis, and autoimmune hepatitis. In steatosis and cirrhosis, the alcoholic etiology should be established based on clinical history, physical examination, and clinical biochemistry evaluations.

Evaluation of the patient with suspected alcoholic hepatopathy should include:

• Accurate assessment of daily and weekly alcohol intake

patterns

• Physical examination to identify the typical signs of

chronic hepatopathies, such as hepatomegaly, spider nevi,

ascites, splenomegaly, gynecomastia, jaundice, and pal-

mar erythema

• Clinical biochemistry evaluation of liver function by mea-

suring AST, ALT, bilirubin, alkaline phosphatase, GGT,

blood cell count, albuminemia, PT, and INR. None of

these tests is diagnostic of alcoholic liver disease, but an

AST/ALT ratio >2 is strongly indicative of alcoholic

etiology

• Biochemical and clinical evaluation of other potential

causes of chronic liver disease by measuring HBsAg,

HBeAg, and anti-HCV antibodies to exclude viral hepatitis

• Ferritin and transferrin saturation to rule out hemochromatosis

• Evaluation of total IgG, ANA, ASMA, and anti-LKM-1 to rule out autoimmune hepatitis.

It should be noted that ferritinemia increases even in the

absence of martial overload in some conditions, including alcoholic hepatitis and acute or subacute hepatitis. It follows that in the patient with acute or subacute hepatitis, it is necessary to wait until the acute event has resolved to assess iron metabolism properly. Moreover, transferrin saturation in alcoholic hepatitis can reach values of 60% or more due to inhibitory action of alcohol on transferrin synthesis. For these reasons, specialist diagnostic tests should be performed if hemochromatosis is suspected.

Other laboratory investigations may be required if, based

on the patient’s medical history, α1-antitrypsin deciency, hyperthyroidism, celiac disease, primary biliary cirrhosis, or primary sclerosing cholangitis is suspected.

Imaging provides evidence of steatosis or cirrhosis.

However, it does not allow to establishthe etiology, which instead can be determined based on the patient’s clinical history and clinical biochemistry evaluation. Theliver biopsy is required when the diagnosis remains uncertain after noninvasive investigations, for example, the clinical and biochemical picture is only partially compatible with alcoholic liver disease (moderate alcohol intake and AST/ALT ratio >1) and other causes cannot be excluded.

Fibrosis

Hepatic brosis is a scarring process in which the extracellular matrix encapsulates the region of the liver parenchyma that has suffered an inammatory insult.Fibrosis develops in almost all patients with chronic hepatopathy, although varying degrees depending on the type of stimulus that generated it and factors related to the host. Fibrosis is a dynamic pathological event, which is reversible in the early stages.

The composition of scar tissue is independent of the type

of insult that led to brosis and involves the presence of macromolecules present in the normal extracellular matrix, including collagen of type I, III, V and IX, bronectin, laminin, and elastin. The transition to a brotic tissue involves a signicant change in matrix composition, with at least a three to tenfold increase in collagen, glycoproteins, proteoglycans, and glycosaminoglycans. These changes in the composition of the extracellular matrix result in the replacement of the normal low-density matrix of the subendothelial space by the interstitial matrix, with important consequences for the function of hepatocytes, stellate cells, and endothelial

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Cause of liver injury

Molecular mediators

Inflammatory phase

Fibrogenesis

Fibrosis resolution

Alcohol abuse

Ethanol

metabolism

Acetaldehyde

T cells

IL-6, IFN-γ, CD40

Quiescent stellate cell

Apoptotic

hepatocytes

Regeneration of hepatocytes

Stimulation

HCV infection

Viral proteins

Core NS3, NS5

Free radicals

TGF-β, TNF-α, EG F, IGF

Activation of hepatic

Accumulation of fibrogenic cells

Myofibroblasts

Apoptotic stellate

cells

Cholestasis

Reduced

excretion of bile

Bile acids

Hepatocytes

stellate cells

TGF-β, TIMP-1, TIMP-3

Reduction of TIMP-1 and -3

MMP-1, MMP-8,

MMP-13

Metabolic syndrome

Altered glycemic homeostasis

Hyperglycemia Adipokynes

TGF-β, TNF-α, IL-6, IGF

Extracellular matrix synthesis

Lipid

accumulation

Kupffer cell

Free radicals

Activated stellate cells

Extracellular matrix degradation

Altered lipid metabolism

FFA

Fig. 11.6 Schematic representation of the mechanisms leading to hepatic brosis. (Copyright EDISES 2021. Reproduced with permission)

cells. When the processes of cell proliferation, deposition of the extracellular matrix, regeneration of the hepatic parenchyma, and inammation occur in a contextual and, above all, uncontrolled manner, a state of brosis is established that can progress into cirrhosis (Fig.11.6). Recently, the knowledge of the molecular mechanisms leading to brosis has

matory stateoccurs, regardless of the degree of extracellular matrix deposition. None of the biomarkers available today are specific for hepatic fibrosis, and inflammatory states at other sites may contribute to increased circulating levels.

Serological markers can be distinguished into:

aroused great scientic interest due to the potential of developing therapies aimed at stopping the progression of brosis.

• Indirect markers reecting changes in liver function.

• Direct markers of brosis, or biomarkers reecting the turnover of the extracellular matrix. Indirect markers

Diagnostic Investigations

The diagnostic approach to liver brosis includes biochemical, imaging, and histopathological evaluations, which are of little help if considered in isolation. Histopathological investigations represent the gold standard for the diagnosis and classication of brosis.

Noninvasive, serological, and imaging investigations (mainly hepatic elastometry) are performed to monitor any brosisprogression.

Many biomarkers have been proposed for predictingfibrosis severity, with variable results. Generally, bio-

include all serological tests, which are indicative of an alteration in liver function, namely AST, ALT, platelet count, basic coagulation parameters (PT and INR), GGT, total bilirubin, α2-macroglobulin, and α2-globulins (mainly haptoglobin). Since these tests, individually, provide rather limited clinical information about the presence or absence of brosis, several panels have been proposed that combine these tests in various ways to increase their diagnostic accuracy. The APRI (AST to Platelet Ratio Index) and the Hepascore are the best

known. markers of hepatic fibrosis reflect matrix turnover, but not the extent of deposition of its components. Therefore, they may increase significantly when a relevant inflam-

The APRI is calculated using the serum AST concentra-

tion, its upper reference limit (URL) used in the laboratory,

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

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and platelet count (PLT) according to the following formula:

PRIAST LSRPLT

The clinical validity of APRI was evaluated primarily in patients with hepatitis C and hepatopathy alcoholic. In patients with hepatitis C, it has been shown that a cutoff of

0.7 is associated with a sensitivity of 77% and a specicity of 72% in predicting signicant brosis, while a cutoff of 1.0 is associated with a sensitivity of 76% and a specicity of 72% in predicting cirrhosis.

The Hepascore is an index calculated based on total bilirubin, GGT, hyaluronic acid, α2-macroglobulin, age, and sex.

The clinical evidence on the use of these scoring systems, although encouraging, is not sufcient to date to consider their use in clinical routine.

Direct markers of liver brosis include biomarkers of collagen synthesis or degradation, extracellular matrix glycoproteins, proteoglycans, and glycosaminoglycans. They can be summarily distinguished into biomarkers associated with extracellular matrix deposition, biomarkers associated with extracellular matrix degradation, and cytokines and chemokines associated with brogenesis (Table11.13).

Serum levels of N-terminal procollagen type III peptide (PIIINP) increase in acute and chronic hepatopathies. They correlate with transaminase and bilirubin levels in cirrhotic patients and histological degree of brosis and inammation in patients with alcoholic hepatopathy, viral hepatitis, and primary biliary cirrhosis. N-terminal procollagen type I peptide (PINP) levels increase in patients with cirrhosis; however, this markeris less accurate than procollagen III-derived peptides in predicting the severity of brosis and the presence of hepatitis. Extracellular matrix degradationis primarily mediatedby metalloproteinases (MMPs). These enzymes are synthesized intracellularly and secreted as proenzymes. Their activation requires proteolytic cutting mediated by cell surface enzymes. Finally, their action is inhibited by tissue inhibitors of metalloproteinases (TIMPs). It has been pro-

Table 11.13 Main biomarkers of brogenesis and hepatic brinolysis

Deposition of the matrix

N-terminal peptide of type I procollagen (PINP) N-terminal peptide of type III procollagen (PIIINP) C-terminal peptide of type III procollagen (PIIICP) YKL-40

Degradation of the matrix

MMP-2 Tissue inhibitor of metalloproteinases (TIMP-1, -2)

Cytokines

TGF-β TNF-α PDGF

posed that the degradation of the hepatic extracellular matrix by MMPs, or the loss of its regulation, is a pathophysiological event in liver brosis. Inammation plays a relevant role in the pathogenesis of brosis, and many cytokines and other mediators of inammation have been directly associated with the processes of cell proliferation and extracellular matrix deposition. For example, TGF-β is among the most potent stimulators of extracellular matrix production by hepatic stellate cells.

In general, evidence on the clinical use of direct labelers has often remained isolated and has not led to denitive conclusions on their use in clinical routine.

Cirrhosis

Cirrhosis is the terminal stage of the chronic pathophysiological process that progresses from steatosis into hepatitis, i.e., an inammatory lesion with inltration of neutrophil granulocytes in the portal spaces and hepatocellular necrosis, and nally into brosis and cirrhosis, caused by the proliferation of broblasts at the site of necrosis and hyperproduction of collagen. Cirrhosis is characterized by the loss of the typicalarchitecture of the liver parenchyma and the formation of regenerative nodules. It is generally considered irreversible in the most advanced stages, in which the only therapeutic possibility is liver transplantation. Cirrhotic patients are at high risk of severe complications that limit their life expectancy. Several pathological conditions can lead to cirrhosis, the most frequent of which are certainly hepatitis C, alcoholic hepatopathy, and nonalcoholic hepatic steatosis, which together account for 80% of cases in the United States (Table11.14).

Severe complications may be observed in cirrhotic patients, whose onset marks the passage from a compensated

Table 11.14 Causes of liver cirrhosis

Main causes

Chronic viral hepatitis Alcoholic liver disease Hemochromatosis Non-alcoholic fatty liver disease (NAFLD)

Less frequent causes

Autoimmune hepatitis Primary and secondary biliary cirrhosis Primary sclerosing cholangitis Use of methotrexate Wilson’s disease α1-antitrypsin deciency Celiac disease Hepatic granulomas Hepatic polycystosis Infections (brucellosis, syphilis, echinococcosis) Hereditary haemorrhagic telangiectasia Portal thrombosis

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Table 11.15

Encephalopathy Absent Grade 1–2 Grade 3–4 Ascites Absent Slight Mild Bilirubin (mg/dL) <2 2–3 >3 Albumin (g/L) >35 28–35 <28 INR <1.7 1.7–2.2 >2.2

Table 11.16

Child-Pugh class Score Interpretation A 5–6 Well compensated cirrhosis B 7–9 Signicant functional impairment C 10–15 Decompensated cirrhosis

Calculation of the Child–Pugh score

Score 1 2 3

Interpretation of the Child–Pugh score

stage to decompensated cirrhosis. These include ascites, esophageal varices with bleeding, spontaneous bacterial peritonitis, hepatic encephalopathy, hepatocarcinoma, hepatorenal syndrome, and hepatopulmonary syndrome. Many of these conditions are consequences of portal hypertension. The most frequent complication of cirrhosis is ascites, a direct consequence of portal hypertension. While in patients with compensated cirrhosis, the average survival is about 12years, the transition to a stage of decompensation determines a worse prognosis and a signicant increase in the mortalityrisk.

In this regard, several predictive models have been formulated to be applied in patients with chronic hepatopathy for prognostic purposes, among which the most popular isthe Child–Pugh classication and the MELD score.

The Child–Pugh classication is based on the presence of encephalopathy, ascites, bilirubinemia, albuminemia, prothrombin time and, bya scoring system ranging from 5 to 15, classies the patient into three categories: Child A, wellcompensated cirrhosis (5–6 points); Child B, signicant functional impairment (7–9 points); Child C, decompensated cirrhosis (10–15 points) (Tables 11.15 and 11.16).

Another model to predict the prognosis of cirrhotic patients is the MELD score (Model for End-Stage Liver Disease), which is based on bilirubinemia, creatininemia, natremia, and INR. This score was initially developed to establish the priority of access to liver transplantation, but it was later extended to different settings. The predictive model underlying the MELD score has undergone various revisions over time, including the insertion of the variable sodium (Na), for which various versions are now available, as summarized in Table11.17. A MELD value >15 represents the degree of severity of the disease below which liver transplantation would not lead to substantial benet. An exception is hepatocarcinoma, for which access to transplant is independent of the MELD score.

Clinical manifestations of cirrhosis include both nonspecic symptoms (anorexia, weight loss, asthenia, fatigue) and

Table 11.17

MELD 9.57 ln [creatinin (mg/dL)]+3.78 ln [bilirubin (mg/

MELD-Na MESO [MELD/Na (mmol/L)]×100 MELD

MELD-Na MELD sodium, MONTH MELD/sodium ratio, iMELD integrated MELD

Formulas for calculating the MELD score

dL)]+11.2 ln (INR)+6.43 MELD+1.59×[135−Na (mmol/L)]

MELD+[età (anni)×0.3]−[0.7×Na (mmol/L)]+100

signs and symptoms of hepatic decompensation (jaundice, pruritus, signs of gastrointestinal bleeding, such as hematemesis, melena, hematochexia, abdominal distension following ascitis, confusional states due to hepatic encephalopathy). The progression of cirrhosis is accompanied by a decrease in mean arterial pressure, which may contribute to the establishment of hepatorenal syndrome and is recognized as a signicantpredictor of mortality in these patients.

Several hematochemical parameters are altered during cirrhosis. Often, the occasional nding of such alterations leads to the suspicion of cirrhosis.The most common abnormalities include increased bilirubin, transaminases, alkaline phosphatase, GGT, INR prolongation, hyponatremia, and thrombocytopenia.

Transaminases are usually moderately elevated in cirrhotic patients. The increase in AST is more signicant than that of ALT.However, the nding of normal transaminases does not ezcludethe diagnosis of cirrhosis. In many forms of chronic hepatitis, except for alcoholic hepatitis, the AST/ ALT ratio is <1. However, as hepatitis progresses to cirrhosis, the AST/ALT ratio may reverse.

Alkaline phosphatase usually increases in cirrhosis up tothree times the upper reference limit. Higher values are an expression of cholestatic diseases, such as primary sclerosing cholangitis or primary biliary cirrhosis.

GGT correlates with alkaline phosphatase in liver disease but lacks any specicity. GGT increases more in chronic alcoholic hepatopathy than other hepatopathies of different etiology. Alcohol induces microsomal GGT expression and GGT release from the hepatocyte.

Bilirubin may be normal in well-compensated cirrhosis but increases as the degree of hepatic decompensation progresses. Increased bilirubin is an unfavorable prognostic sign in patients with primary biliary cirrhosis.

Albumin is synthesized exclusively by the liver. Its serum levels decrease as the biosynthetic capacity of the liver declines as cirrhosis progresses. For this reason, albuminemia is helpful in determining the severity of cirrhosis. Hypoalbuminemia is not specic to liver disease but can also be observed in nephrotic syndrome, protideless enteropathies, and malnutrition.

Most of the proteins involved in the hemostatic process are synthesized by the liver. For this reason, the prothrombin time and INR reect the degree of hepatic dysfunction. A

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Beta-gamma bridge

Albumin

α1-globulins

Fig. 11.7 Electrophoresis pattern of a cirrhotic patient in which the

β2-globulin band overlaps the γ-globulin band, forming the typical beta-gamma bridge. The values of the single fractions were albumin,

38.4% (IR: 54.5–65); alpha-1, 2.5% (IR: 3.1–6); alpha-2, 5.1% (IR:

7.1–11.8); beta-1, 4.2 (IR: 5–7.2); beta-2, 9.9 (IR: 3.2–6.5); gamma,

39.9 (10.5–18.8). The patient had the following biochemical-clinical

2-globulins

prolongation of the INR is considered an unfavorable prognostic index in cirrhotic patients.

Hyponatremia is common in patients with cirrhosis and ascites and results from reduced water excretion caused by increased antidiuretic hormone (ADH) release.

Patients with cirrhosis often present with different haematological anomalies, including varying degrees of cytopenia. Thrombocytopenia is the most frequent abnormality; leukopenia and anemia occur in more advanced stages. Thrombocytopenia is primarily caused by portal hypertension related to splenomegaly. An enlarged spleen may result from the sequestration of approximately 90% of circulating platelets. However, it is rare for platelet counts to be <50,000/ mL and, unless complicated by coagulopathy, is not a clinical problem.

Anemia has a multifactorial origin. Probable causes include acute and chronic blood loss, folate deciency, direct alcohol toxicity to erythrocyte membranes, splenomegaly, bone marrow suppression (hepatitis-associated aplastic anemia), inammation-associated anemia, and hemolysis.

Leukopenia and neutropenia result from splenic sequestration.

On serum protein electrophoresis, an increase in globulins is frequently found with the typical beta-gamma bridge (Fig.11.7).

Patients with suspected cirrhosis undergo ultrasonography of the abdomen and the abovementioned laboratory

β1-globulins

β2-globulins

values: albumin, 27.3 g/L (IR: 35–52); protidemia, 71.2 g/L (IR: 66–87); ferritin, 1977ng/mL (IR: 30–400); transfer, 158mg/dL (IR: 200–360); AST, 47U/L (IR: 0–37); ALT, 15U/L (IR: 0–41); total bilurubin, 12mg/dL (<1.2); alpha-fetus-protein, 2.99μg/L (IR: 0–7); INR

2.04; APTT, 41seconds (IR: 24–36)

γ-globulins

tests, which are often sufcient, together with a complete history and physical examination, to establish the diagnosis. However, diagnosis must be conrmed by liver biopsy in doubtful cases.

Alcoholism

Introduction

Ethyl alcohol, or ethanol (CH3CH2OH), is a small watersoluble molecule rapidly and completely absorbed from the gastrointestinal tract.The lungs can also absorb ethanol vapors.

Ethanol is mainly present in alcoholic beverages; small quantities are produced by the intestinal bacterial ora (0.1–2mg/100g). In addition, invitro studies have demonstrated its production in various bodytissues, including the brain.

Ethanol has a high energy content, 7kcal/g, an intermediate value between carbohydrates and lipids, but unlike the latter that are accumulated, ethanol is metabolized or eliminated through urine and exhaled air.

The chronic and/or excessive ingestion of ethanol causes alcoholism, a metabolic disease that mainly affects the liver, the digestive system (impaired digestion and absorption), and the respiratory system, with alterations in respiratory (ventilation, diffusion, vascularization, and surfactant syn-

Ethanol

Acetate

r ethanol

Deh

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thesis) and nonrespiratory (ciliary apparatus, macrophages, lymphocytes) function, and the central and peripheral nervous system (the main effects of ethanol are on the central nervous system, where the depressive actions are similar to those of volatile anesthetics).

Ethanol Metabolism

Ingested ethanol is rapidly absorbed into the digestive system by passive diffusion. Ethanol is measurable in the bloodstream as early as 5 minutes after ingestion, and the peak concentration is reached after 30–90minutes.

After absorption, ethanol is predominantly metabolized oxidatively (90–98%), at a constant rate over time (order 0 kinetics) of 100 mg/kg/hour. Most of the ethanol intake (>80%) is metabolized in the liver; the remaining part is metabolized in the kidney, lung, stomach, intestines, brain, and muscles.

Elimination occurs:

• Through the liver, where it is converted to CO2 and H2O

(>90%)

• Through the respiratory route (1–4%)

• Renal (1–2%) (ethanol stimulates diuresis)

• In the milk

• In sweat

Ethanol is mainly metabolized through two oxidation reactions: the rst converts it to acetaldehyde, and the second converts acetaldehyde to acetate.

In the hepatocyte, at least three alternative enzymes catalyze the rst oxidation reaction (Fig.11.8):

• Alcohol dehydrogenase (ADH)

• Microsomal oxidant ethanol system (MEOS)

• Catalase

ADH is the most important enzyme in ethanol metabolism. It is localized in the cytosol and is dependent on NAD+ and zinc.

ADH is encoded by seven gene loci (ADH1–ADH7), located on the long arm of chromosome 4, whose allele frequency differs in different ethnicities. In addition, gene variants associated with altered (accelerated or reduced) ethanol oxidation have been identied that may explain different alcohol tolerance; for example, Eastern peoples (Japanese and Chinese) have poor alcohol tolerance due to the high frequency of a polymorphic variant associated with reduced ADH activity.

MEOS is a mixed-function oxygenase associated with the smooth endoplasmic reticulum (SER) of the hepatocyte; it is cytochrome P450 and NADPH-dependent. It functions at high ethanol concentrations (chronic intoxication), following hypertrophy of the SER (hypertrophy is an adaptive phenomenon that improves the liver capacity to metabolize ethanol) and is induced by ethanol itself. This enzyme can also oxidizeother substances, such as drugs (paracetamol); therefore, excessive stimulation of this system leads to important changes in the metabolism of these substances. Alcoholic patients are more sensitive to these types of substances to the point of suffering serious hepatic injury even at low drugdoses.

Catalase is an enzyme in peroxisomes; it has a limited effect on ethanol metabolism due to the limited availability of hydrogen peroxide in the hepatocyte.

Under low ethanol intake, ADH is the only enzyme responsible for the ethanoloxidation to acetaldehyde; however, MEOS and catalase also function at high ethanol concentrations.

Most of the acetaldehyde produced in the hepatocyte is normally oxidized to acetate by the mitochondrial NADdependent acetaldehyde dehydrogenase, which has a high afnity for acetaldehyde and is highly specic. The remaining acetaldehyde is oxidized by cytosolic acetaldehyde dehydrogenase and partly by aldehyde oxidase and xanthine

Fig. 11.8 Ethanol metabolism. (Copyright EDISES 2021. Reproduced with permission)

Alcohol

ydrogenase

(ADH)

NAD

Catalase

NADH + H

Aldehyde

dehydrogenase

(ALD)

H2O

2 H2O2 H2O

NADPH + H

Acetaldehyde

NAD

NADH + H

NADP

Microsomal

system fo oxidation (MEOS)

118

Ethanol

Acetaldehyde

Acetate

The Krebs cycle

123410–30 days

Blood ethanol

Blood CDT

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oxidase. At very high concentrations of ethanol, not all of the acetaldehyde can be converted to acetate, and therefore, this passes into the circulation, with consequent lesions at various levels.

Most of the acetate synthesized in the liver is released into the circulation.Itreaches the extra-hepatic tissues, where it is rapidly converted to acetyl-CoA and oxidized to carbon dioxide (CO2) in the Krebs cycle. A small amount of acetate, however, is converted hepatically to acetyl-CoA by acetyl- CoA synthetase and then oxidized to CO2 or used for ketone bodies or fatty acidssynthesis.

Very small amounts of ethanol are eliminated via the urinary or biliary tract following conjugation with glucuronic acid or sulfuric acid. Finally, a tiny proportion of ethanol (<2%) may be excreted in an unmodied form via the kidneys and lungs; this proportion increases with massiveethanol ingestion.

Ethanol can induce various biochemical alterations, including increased production of NADH, with increased NADH/NAD+ ratio and, therefore, reducing power:

NAD+NADH + H

Lactic acid (increase)

Lactic

acidosis

Pyruvic acid

(decreases)

Hypogly-

cemia

Fatty Acid

Tr iglycerides

Fatty liver,

hyperlipemia

M. Ciaccio et al.

NAD+NADH + H

Electrons to the

respiratory

chain

slows down

Acetyl-CoA

increases

Ketosis

• In fasting, the change in the balance of lactate dehydroge-

nase to lactate rather than pyruvate, with a tendency to

lactic acidosis and hypoglycemia (from impaired gluco-

neogenesis and reduced glucose uptake).

• In the postprandial, transient hyperglycemia due to the

inhibition of glycolysis at the level of glyceraldehyde- 3-

phosphate dehydrogenase.

• The inhibition of β-oxidation of fatty acids and the

consequent increase in the liver of fatty acids, which

are converted into triglycerides; is reected in the

increase in the hepatic synthesis of very low-density

lipoproteins (VLDL) and denes their deposition in the

liver (hepatic steatosis), as well as the increase in their

plasma concentration. In addition, the increased arrival

of acetyl-CoA to the liver results in increased ketogen-

esis (due to oxalate deciency following reduced pyru-

vate availability).

The high production of acetaldehyde, on the other hand, leads to an increased release of vascular prostacyclin (vasodilatory and antiplatelet action– protective effect of small doses of ethanol against vascular disease); acetaldehydetubulin binding, which determines a decit in the polymerization of microtubules with the consequent reduced hepatic secretion of proteins and an increase in intracellular oncotic pressure and swelling of the hepatocytes; an increase in membrane lipid peroxidation; thebinding with various proteinsleading to the activation of liver theimmune response against the acetaldehyde–protein complex (Fig.11.9).

inary ethanol

inary ETG

Fig. 11.9 Metabolic effects of ethanol. (Copyright EDISES 2021. Reproduced with permission)

Alcohol-Related Clinical Alterations

Excessive voluntary ingestion of ethyl alcohol is called alcoholism or ethylism and can appear in an acute or chronic form. A state of drunkenness characterizes the acute form. The chronic form, on the other hand, represents a true addiction and can lead to early death. Alcoholism must be considered one of themost signicant issues for public health, which involves, in addition to the state of physical and mental health, also the social relationships of the individual.

The main alcohol-related clinical alterationsare:

• Alcoholic gastritis

• Increased incidence of peptic ulcer

• Gastrointestinal bleeding

• Pancreatitis

• Cardiomyopathy

• Cardiac arrhythmias

123410–30 days

Blood ethanol

Blood CDT

11 Liver: FromBiochemistry toClinical Biochemistry

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Table 11.18 Biomarkers of alcohol use

Biomarkers Acronymous Ethanol EtOH Blood

Ethylglucuronide EtG Urine

Carbohydrate-decient transferrin

Gamma-glutamyltransferase GGT Serum/plasma Sensitive marker of alcohol consumption, liver dysfunction and oxidative

Median corpuscular volume MCV Blood Typically increased in alcoholics. It normalizes after 2–4months. Alanine and aspartate aminotransferase

CTD Serum

ALT and AST

Biological sample Characteristics

Urine

Serum Cerebrospinal uid Hair Nails

Cerebrospinal uid

Serum/plasma Used for the screening of liver dysfunction in subjects consuming alcohol.

Limited to the conditions in which ethanol is still in circulation.

Minor metabolite of ethanol. It remains positive in the urine for 2–5days after taking ethanol

Specic marker of chronic alcohol use.

stress. It normalizes after 2–3weeks.

The AST/ALT ratio increases in alcoholic liver disease.

• Fetal alcohol syndrome

• Wernicke–Korsakoff syndrome

• Alcoholic steatosis

inary ethanol

inary EtG

• Alcoholic hepatitis

• Cirrhosis of the liver

119

Biomarkers ofAlcoholism

Several biochemical markers of alcohol abuse, both acute and chronic, have been proposed and can be measured in urine and/or blood. They represent a tool to assess the amount and mode (chronic or acute) of alcohol consumption, andthe damage induced on the body by alcoholism. Biomarkers can be classified as direct, i.e., derived directly from the metabolism of ethanol, and indirect, which are released due to alterations induced by ethanol. The latter is characterized by low diagnostic sensitivity and specificity because it increases significantly only after high and regular intake of alcohol, and its levels may vary in response to factors unrelated to ethanol.

Alongside established biomarkers, such as aspartate aminotransferase, alanine aminotransferase, γ-glutamyltransferase, and mean corpuscular volume of erythrocytes, which are positive only in advanced states of alcohol-related diseases, new, earlier, and more specic markers have been identied (Table 11.18), the main ones of which are (Fig.11.10):

• Blood ethanol (EtOH)

• Urinary ethanol (EtOH)

• EtG (ethylglucuronide)

• CDT (carbohydrate transferrin)

Fig. 11.10 Detection times of the biomarkers of alcoholism. (Copyright EDISES 2021. Reproduced with permission)

Table 11.19

Blood ethanol (mg/dL) Interpretation

≥150 >100 Indicative of alcoholism ≥150

If it can be safely excluded that such high concentrations are not due to

acute ethanol intoxication

Interpretation of blood ethanol concentration

Indicative of excessive alcohol consumption

Indicative of risky drinking, tolerance, and possible addiction

Blood Ethanol

Circulating ethanol levels are a direct and reliable marker of recent alcohol intake. In addition, assessment of blood ethanol values can give insight into long-term ethanol consumption patterns (Table11.19).

Ethanol has a short half-life, about 30minutes, and there-

fore, its presence can only be detected for a short period.

Urinary Ethanol

Ethanol peaks in the urine 45–60 minutes after ingestion. Ethanol levels in the urine are generally higher than the corresponding blood levels; this is true in the elimination phase, after ethanol has reached its peak in the blood and, therefore, its circulating levels begin to decline. In addition, alcohol in urine can be detected for a more extended period (up to

120

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M. Ciaccio et al.

1–2hours longer) than in blood because the urine remains in the bladder for a period. Urinary ethanol is characterized by marked interindividual uctuations.

The presence of alcohol in the urine indicates recent previous intake but may not be related to the degree of intoxication observed at the time of sample collection. The level of ethanol inthe sample refers only to the average concentration of alcohol in the blood during the time it takes for the urine sample to accumulate in the bladder, not to the concentration of alcohol in the blood at the time of collection.

False-negative results may be caused by the volatility of the alcohol. Urine alcohol concentrations may decrease by 10–25% during each hour before the urine sample is analyzed.

Ethylglucuronide (EtD)

Ethylglucuronide is a direct minor metabolite of ethanol and is considered highly specic for the assessment of recent alcohol intake. In particular, it is an ethanol conjugation product formed by reaction with activated glucuronic acid (uridin-5′-diphospho-β-glucuronic acid [UDPGA]) mediated by the uridine-diphosphate glucuronosyltransferase (UGT)enzyme.

EtG is in various biological uids, tissues, and hair. However, it is generally measured in urine. EtG can remain positive for several days after the discontinuation of ethanol intake and, therefore, may provide added value in assessing recent alcohol consumption. In particular, in urine remains for 40–60hours after alcoholic intake. In the blood, instead, it is detectable up to 14hours after the intake; an occasional intake of alcohol is enough to exceed the threshold of

0.5mg/L.

Some studies have indicated diagnostic applications of EtG in postmortem assessments of alcohol consumption and fetal alcohol exposure or in patients awaiting liver transplantation.

Polymorphic variants in genes encoding UGT may have a signicant impact on the ability of humans to synthesize EtG and may, therefore, explain interindividual differences in EtG levels after alcohol consumption.

Carbohydrate Transferrin (CDT)

Carbohydrate transferrin is a specic marker of chronic alcohol abuse.

Transferrin is a serum protein that transports iron in the circulation to the target organs (bone marrow, liver, and spleen). From a structural point of view, transferrin is a glycoprotein consisting of a polypeptide with two polysaccharide chains linked with sialic acid residues. The addition of sialic acid occurs through a posttranslational reaction mediated by an enzymatic system with ethanol-dependent glucosyltransferase activity; ethanol and its metabolite, acetaldehyde, reduce the enzymatic activity of this system.

There are several forms of transferrin, which differ in the number of iron atoms carried (0–2), the primary structure (genetically determined), and the number of sialic acid residues (0–8). Most circulating transferrin (>80%) contains four sialic acid residues (tetrasialotransferrin, TeST); the form with two residues (disialotransferrin, DST) is physiologically present in amounts <2%, while the desialylated form (asialotransferrin, aST) is almost absent. In the case of massive and continuous ethanol intake, the desialylated fraction increases. The term CDT refers to the set of low sialic acid transferrins and, particularlyto the aST and DST forms. CDT has a longer half-life (10days) than transferrin in the circulation (7days).

CDT elevation requires the consumption of at least 50–80g of ethanol per day for several weeks and, therefore, has low sensitivity when used as a screening tool in the general population. However, in alcohol-dependent patients, it is sufciently sensitive to detect relapse and monitor sobriety.

Liver Cancers

There are numerous types of primary liver cancers, both benign and malignant (Table11.20). Most of them arise from the main cells constituting the organ, such as hepatocytes (hepatocarcinoma), biliary epithelial cells (cholangiocarcinoma and biliary cystadenocarcinoma), endothelial cells (angiosarcoma, epithelioid hemangioendothelioma), or combinations of these cells with various mesenchymal cells (e.g., hepatoblastoma). These lesions generally do not spread to other organs but within the liver itself, giving rise to multifocal tumors.

In addition, due to its high vascularity, the liverhas a high incidence of secondarycancers, i.e., metastases from cancers originating in other organs, especially the gastrointestinal tract. Epidemiological data show that up to 50% of patients with colorectal cancer are diagnosed with or develop distant metastases, mainly hepatic, in the years following resection of the primarycancer.

Benign cancers are quite frequent in the population (up to 20%) and are usually discovered incidentally during investi-

Table 11.20 Benign and malignant liver lesions

Benign lesions Malignant lesions

-Hepatic hemangioma

-Hepatic adenoma

-Focal nodular hyperplasia

-Idiopathic portal hypertension

-Regenerative nodules

-Inammatory pseudotumor (rare benign liver tumor consisting of proliferating brous tissue inltrated by inammatory cells)

-Hepatocarcinoma

-Cholangiocarcinoma

-Fibrolamellar carcinoma

-Hepatoblastoma

-Mesenchymal tumors:

-Epithelioid hemangioendothelioma

-Angiosarcoma

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