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Hepatic Blood Flow
The portal vein, formed by the splenic and superior mesenteric veins, provides two-
thirds of the hepatic blood ow, with the hepatic artery providing the rest [2]. Mixed
arterial and venous blood circulate through the sinusoids [3], which converge into
the hepatic veins to drain into the superior vena cava, except as noted above for the
caudate lobe [1].
Liver Lymphatics
The initial lymphatic vessels arise in the portal tracts. There is a capsular lymph
network; it is unclear whether these two networks communicate with each other.
Lymphatics drain lymph from interstitial spaces within the liver, most notably, the
space of Disse. The liver provides 25–50% of the lymph that enters the thoracic duct
[4]. The increase in venous pressure results in increased capillary ltration and
hence, increased lymph ow, as it happens in portal hypertension. There are large
lymphatic vessels in the hepatic hilum through which lymph circulates toward the
cisterna chyli [4].
Liver Histology
The hepatocyte is the parenchymal cell that carries the liver function and comprises
70% of the liver mass.
The nonparenchymal liver cells include liver sinusoidal endothelial cells that
comprise 50% of the population; Kupffer cells, 20%; lymphocytes, 25%; biliary
epithelial cells, 5%; and hepatic stellate cells, 1%.
The hepatic sinusoids are channels throughout the liver through which blood
ows. Sinusoidal endothelial cells form the walls of the hepatic sinusoids, which
characteristically lack a basement membrane, i.e., they have fenestrae to allow for
an intimate contact with the space of Disse [5]. The space of Disse is located
between the endothelial cells and the sinusoidal surface of the hepatocyte.
Projections from the hepatocytes lie in the space of Disse, through which sub-
stances circulating in the sinusoidal stream are taken up by the parenchymal cells
for metabolism.
The Kupffer cells are liver macrophages that clear circulating endotoxin and
other exogenous substances perceived as foreign or injurious to the body [6].
They promote regulatory T cells to inhibit cytotoxic T cells in physiological con-
ditions [7].
The lymphocyte component of the liver is comprised of natural killer and natural
killer T cells, which are pivotal in the immune response and lymphocyte recruitment [8].
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Biliary epithelial cells line the intrahepatic and extrahepatic bile ducts and mod-
ify the composition and ow of the bile formed by the hepatocyte [9]. Biliary epi-
thelial cells can also participate in liver regeneration and immune-mediated
processes [10].
The hepatic stellate cells are perisinusoidal cells that store vitamin A in the nor-
mal liver. In response to liver injury, they are activated and turn into alpha-smooth
muscle actin-expressing contractile myobroblasts increasing portal pressure by
their effect on the vasculature. In addition, when activated, they participate in
mitogen- mediated proliferation, increased brogenesis, and abnormal matrix degra-
dation [11].
Afferent and efferent nerve bers innervate the liver. The portal tract contains
parasympathetic and sympathetic bers; the latter coursing into the liver sinusoids.
Hepatic afferent bers are considered to participate in osmosensation and metabolic
sensing. Hepatic efferents are believed to regulate hepatic vasculature tone, metabo-
lism, and liver regeneration. Neuropeptides and neurotransmitters regulate the func-
tion of the biliary epithelium. A role for the autonomic nervous system in the
activation of hepatic stellate cells has been suggested [12].
Liver Organization
The liver is organized in hexagonal, one cell thick plates of 15–25 hepatocytes,
known as hepatic lobules [13]. The portal triads, comprised of a vein, artery, bile
duct, and nerve, are located at the apices of the hexagon. Between cell plates, mixed
arterial and venous blood circulates through the hepatic sinusoids from the portal
tract to the central vein through which a functional gradient, known as metabolic
zonation, regulated by Wnt/β-catenin signaling [14] exists. Zone 1 is periportal, fol-
lowed by zone 2 and zone 3, which is pericentral [15]. The acinus is a term used to
describe the smallest functional liver unit, with acinar zones 1, 2, and 3 being
located in the same area as those of the lobule.
Oxygenation, beta-oxidation, gluconeogenesis, glycogen synthesis from lac-
tate, and ureagenesis predominantly occur in zone 1. Triglyceride synthesis,
lipogenesis and ketogenesis, glycolysis, and glycogen synthesis from glucose
occur in zone 3. However, cells from the three zones have the exibility to pro-
vide functions that may be impaired by injury or fasting, for example, in other
zones [15].
Liver Function
The liver is a generous organ. It processes substances from the splanchnic circula-
tion prior to their availability to the systemic circulation. The function of the liver
includes the synthesis and secretion of proteins, transport and biotransformation of
1 The Liver
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drugs, production of bile, bile acids and heme, metabolism of carbohydrates, lipids
and lipoproteins, amino acids, and metals and trace elements, in addition to urea
production, pH regulation, and excretion of porphyrins [15, 16].
References
1. Bismuth H, Aldridge MC, Kunstlinger F.Structure of the liver. In: McIntyre N, Benhamou J-P,
Birher J, Rizzetto M, Rodes J, editors. Oxford textbook of clinical hepatology, vol. 1. Oxford:
Oxford University Press; 1991. p.3–11.
2. Tystrup N, Winkler K, Mellemgaard K.Determination of arterial blood ow and oxygen sup-
ply in man by clamping the hepatic artery during surgery. J Clin Invest. 1962;41:447–54.
3. Wake K, Sato T. “The sinusoid” in the liver: lessons learned from the original denition by
Charles Sedgwick Minot (1900). Anat Rec. 2015;298:2071–80.
4. Ohtani O, Ohtani Y.Lymph circulation in the liver. Anat Rec. 2008;291(6):643–52.
5. Elvevold K, Smedsrød B, Martinez I.The liver sinusoidal endothelial cell: a cell type of contro-
versial and confusing identity. Am J Physiol Gastrointest Liver Physiol. 2008;294(2):G391–400.
6. Krenkel O, Tacke F.Liver macrophages in tissue homeostasis and disease. Nat Rev Immunol.
2017;17(5):306–21.
7. Heymann F, Peusquens J, Ludwig-Portugall I, Kohlhepp M, Ergen C, Niemietz P, Martin C,
van Rooijen N, Ochando JC, Randolph GJ, Luedde T, Ginhoux T, Kurts C, Trautwein C,
Tacke F.Liver inammation abrogates immunological tolerance induced by Kupffer cells.
Hepatology. 2015;62(1):279–91.
8. Racanelli V, Rehermann B. The liver as an immunological organ. Hepatology. 2006;43(2
Suppl 1):S54–62.
9. Boyer JL.Bile formation and secretion. Compr Physiol. 2013;3(3):1035–78.
10. Banales JM, Huebert RC, Karlsen T, Strazzabosco M, LaRusso NF, Gores GJ.Cholangiocyte
pathobiology. Nat Rev Gastroenterol Hepatol. 2019;16(5):269–81.
11. Puche JE, Saiman S, Friedman SL.Hepatic stellate cells and liver brosis. Compr Physiol.
2013;3(4):1473–92.
12. Jense KJ, Alpini G, Glaser S.Hepatic nervous system and neurobiology of the liver. Compr
Physiol. 2013;3(2):655–65.
13. Rappaport AM, Borowy ZJ, Lougheed WM, Lotto WN.Subdivision of hexagonal liver lob-
ules into a structural and functional unit: role in hepatic physiology and pathology. Anat Rec.
1954;119:11–33.
14. Gebhardt R, Matz-Soja M.Liver zonation: novel aspects of its regulation and its impact on
homeostasis. World J Gastroenterol. 2014;20(26):8491–504.
15. Trefts E, Gannon M, Wasserman DH.The liver. Curr Biol. 2017;27(21):R1147–R51.
16. McIntyre N, Benhamou J-P, Birher J, Rizzetto M, Rodes J.Function of the liver. In: Oxford of
clinical hepatology, vol. 1. Oxford: Oxford University Press; 1991. p.31–227.
N. V. Bergasa
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5© The Author(s), under exclusive license to Springer-Verlag London Ltd., part
of Springer Nature 2022
N. V. Bergasa (ed.), Clinical Cases in Hepatology,
https://doi.org/10.1007/978-1-4471-4715-2_2
Chapter 2
Approach tothePatient withLiver Disease
NoraV.Bergasa
The approach to a patient with liver disease should be guided by an inquisitive
mind, judicious yet bold use of diagnostic blood tests, and a prudent choice of inva-
sive procedures. The identication of a chief complaint, a complete medical history,
and a thorough physical examination form the basis of the approach to a patient with
liver disease. The identication of risk factors for liver disease is particularly
important.
Patients with liver disease may present with subtle symptoms, the recognition of
which will alert the clinician to hepatic pathology. Other times, the quality of life of
the patients may be markedly impaired [
1]. It is implicit in the title of this chapter
that the clinician knows that the patient has liver disease, e.g., a referral made to the
hepatology clinic. However, a suggestion of liver disease is often laboratory data
derived from health maintenance efforts or obtained for other medical reasons.
Thus, it is the prepared mind that will recognize a connection between symptom(s)
or abnormal laboratory tests and liver disease.
The range of liver injury varies from inammation to brosis and cirrhosis, char-
acterized by a disruption of the liver architecture by regenerating nodules. Liver
failure is characterized by impaired liver function, which can be the presentation of
advanced liver disease, or it can be acute and fulminant. The majority of liver condi-
tions that lead to long-term complications, however, tend to be chronic and some
progress slowly; a detailed investigation is necessary to arrive at the correct diagno-
sis and treatment.
N. V. Bergasa (*)
Department of Medicine, H+H/Metropolitan, New York, NY, USA
New York Medical College, Valhalla, NY, USA
Hepatology, H+H/Woodhull, Brooklyn, NY, USA
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Symptoms ofLiver Disease
The identication of a chief complaint and the exploration of its onset, duration, and
characteristics are necessary.
Jaundice
Recognized as a sign of liver disease, jaundice may be identied by the patient and
hence be part of the chief complaint as “yellow eyes” (Fig.2.1). In general, it is a
good indication that some aspect of bilirubin metabolism is altered (e.g., bilirubin
availability, uptake, conjugation, or excretion).
Fatigue
Fatigue is a manifestation of liver disease; its cause is unknown. It is a prevalent
symptom of patients with primary biliary cholangitis (PBC), reported to occur in
80% [2, 3]. Like pruritus, fatigue can precede the diagnosis of PBC.In an internet-
based survey of patients with PBC who were members of the PBCers organization,
fatigue was experienced by 85% of the patients, and it preceded the diagnosis of
PBC in 83% of patients [4]. Fatigue does not correlate with the degree of liver dis-
ease in PBC. Hypothyroidism and depression, which manifest themselves with
decreased energy levels, can coexist in patients with PBC; accordingly, a full
workup to exclude such comorbidities is necessary for the approach to patients with
suspected or documented PBC.
Pruritus
Pruritus or itch can be a manifestation of liver disease, in particular of those charac-
terized by cholestasis (i.e., impaired secretion of bile). It is inferred that pruritus
results from the accumulation of substances normally excreted in bile and that, as a
result of cholestasis, accumulate in tissues. The nature of the pruritogen(s) is
Fig. 2.1 Icteric
conjunctivae (arrow) and
pterigum (arrow head) in a
patient with
decompensated liver
disease in association with
alcohol use disorder
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unknown. It has been hypothesized that the pruritus of cholestasis is mediated, at
least in part, by increased opioidergic neurotransmission; the amelioration of this
type of pruritus by opiate antagonists supports this hypothesis [5, 6]. It is important
to appreciate that pruritus (and fatigue) can precede the diagnosis of liver disease by
years [4].
Poor Appetite andWeight Loss
Poor appetite may accompany the presentation of acute liver disease. Patients with
advanced liver disease may also present with a chronic history of poor appetite [7]
and either weight loss or muscle wasting [8]. In advanced liver disease, weight loss
may not be a reliable indicator of liver disease as uid retention may compensate for
the loss of muscle, giving an equivocated weight.
Abdominal Pain
A questionnaire-based study reported that abdominal pain was experienced more
frequently by patients with liver disease than by the control group over 1month [9].
The pain was worse after meals. It has been written that stretching of Glisson’s
capsule from “liver inammation” results in pain in the liver area; this statement is
difcult to conrm in a controlled fashion. In contrast, right upper quadrant pain
secondary to biliary colic and acute cholecystitis must be considered in patients
with liver disease. The prevalence of gallstones is higher in patients with cirrhosis
than in non-cirrhotic subjects.
Alterations intheSenses ofTaste andSmell
Taste abnormalities (e.g., hypogeusia and dysgeusia) are recognized complications
of liver disease [10]. An interesting observation, initially reported in patients with
acute hepatitis B, is the loss of appetite for cigarettes in smokers; this nding is not
specic for hepatitis B, and it may be due to a perverted sense of taste from liver
inammation [11]. Impaired gustatory function with decreased sensitivity for detec-
tion of salt, sweet, and sour and for recognition of bitter, salt, sweet, and sour, and a
decrease in the mean value of a gustatory score have been reported in patients with
cirrhosis [12].
The serum concentrations of certain elements, including magnesium, zinc, and
vitamin A have been reported to be decreased in patients with liver disease and an
altered sense of taste [12]. A central mediation of taste abnormalities in patients
with liver disease has been proposed [13]. A report by a patient with acute
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drug-induced hepatitis equating the taste of chocolate to that of lard should tell the
reader how inconvenient this symptom can be, especially to a chocolate lover
(NVBergasa, 2004, unpublished). Hyposmia can be associated with cirrhosis and
was reported in association with hepatic encephalopathy [14]. In a study that
included nine patients, hyposmia resolved after liver transplantation [15].
Personality Changes andSleep Disturbances
One of the most dramatic manifestations of decompensated liver disease is hepatic
encephalopathy, characterized by inhibitory neurotransmission [16, 17]. Its presen-
tation can be subtle or orid [18]. The reversal of the sleep pattern is well recog-
nized, with patients reporting insomnia and inability to stay awake during the day,
confusion, and cognitive deciencies [16, 19]. Family members may report person-
ality changes, including combativeness.
Dyspnea
Decreased exercise tolerance and shortness of breath in patients with liver disease
may be secondary to hepatopulmonary syndrome, porto-pulmonary hypertension,
and cardiomyopathy [20, 21], the latter traditionally associated with alcohol abuse
[22] and recently being inconsistently documented as a complication of chronic
hepatitis C infection [23, 24]. A recent study that addresses specically dyspnea in
patients attending a pretransplant clinic did not nd a correlation between the
Medical Research Council scale of dyspnea (mMRC) and the MELD score, or dura-
tion of disease and MELD score or mMRC [25]. Dyspnea can also result from
impaired diaphragmatic excursion due to ascites [26] or hepatic hydrothorax [27].
Bleeding
A history of gastrointestinal bleeding, including hematemesis, melena, or hemato-
chezia, may identify patients with portal hypertension [28].
Stool Characteristics
Jaundice associated with acholic stools (e.g., pale), resulting from decreased bile
pigments in feces, suggests biliary obstruction. In liver diseases characterized by
profound cholestasis, the critical micellar concentration of bile acids is reduced in
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the small intestine [29]; hence, diarrhea from fat malabsorption and, in some cases,
from maldigestion may ensue. Diarrhea is a manifestation of inammatory bowel
disease, which can be associated with primary sclerosing cholangitis and
cholestasis.
Vision Disturbance
Deciency in vitamin A usually manifests itself as an impaired visual adaptation to
darkness, of which patients may not be aware. Patients with liver disease may be
decient in vitamin A because of malabsorption and decreased availability of
retinol- binding protein. In addition, there may be impaired release of vitamin A
from liver stores [30].
Bone Pain andFractures
Pain in the long bones (e.g., tibia) and joints, sometimes associated with clubbing,
is suggestive of hypertrophic osteoarthropathy, a complication of cirrhosis [31]. A
dramatic presentation of liver disease of the cholestatic type can be bone fractures
from osteoporosis, the etiology of which is unknown.
Pain
Peripheral neuropathy manifested by numbness, weakness, and neuropathic pain
can be a symptom of liver disease due to cholestasis; in adults, this manifestation is
rare. Xanthomatous neuropathy from lipid deposition on peripheral nerves associ-
ated with hyperlipidemia from profound cholestasis is well described [32, 33].
Hyperpigmentation
Patients may note skin darkening. Hyperpigmentation is a complication of liver
disease, mainly of the cholestatic type; its pathogenesis is unknown. Increased
availability of a melanocyte-stimulating hormone has been proposed as a contribut-
ing factor [34].
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Vascular Ulcers
Leg ulcers can occur in patients with liver disease and are usually considered sec-
ondary to venous insufciency. However, the healing of leg ulcers in association
with a transjugular intrahepatic portosystemic shunt, i.e., a decrease in portal pres-
sure, in patients with decompensated cirrhosis has been reported [35], and in asso-
ciation with treatment of portal hypertension from thrombotic disease [36]; the
existence of a hepatodermal syndrome was proposed [35].
Chills andRigors
Chills and rigors are manifestations of infection, which can complicate the course
of liver disease as spontaneous bacterial peritonitis in patients with ascites, an
infected biliary tree in patients with primary sclerosing cholangitis, and meningitis
[37, 38].
Dark Urine
Dark brown urine suggests bilirubinuria and it indicates hyperbilirubinemia and
suggests the presence of liver damage; the nding can precede jaundice.
Sexual Dysfunction andDisinterest
Decreased libido and impotence in men is a manifestation of cirrhosis. Men with
cirrhosis secondary to alcohol have been reported to have lower serum concentra-
tions of testosterone and higher serum concentrations of gonadotrophins than
patients without a history of alcohol abuse. In these patients, hypogonadism may
result from the toxic effect of alcohol and its metabolites on the gonads and estro-
gens’ systemic effect on the hypothalamic–pituitary–gonadal axis [39]. Cure of
chronic HCV infection was associated with improved sexual health [40].
In women, important contributors to lack of interest in sexual activities have
been reported to be depression and fatigue.
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Muscle Cramps
Mostly nocturnal, muscle cramps affecting the calves, toes, and ngers can compli-
cate cirrhosis and have a marked negative impact on the quality of life [41, 42]. The
pathogenesis is unknown.
Identication ofRisks forLiver Disease
Activities that involve contact with blood and body uids are risks for acquiring
viral hepatitides [43–46]. Subjects at risk for having contracted viral hepatitides
(e.g., hepatitis C, B, and delta hepatitis) include those with a history of blood trans-
fusions prior to 1992, intravenous injections of illicit drugs, even in the distant past,
subjects on chronic hemodialysis, and individuals who received other blood prod-
ucts (e.g., clotting factors) prior to 1987. Body piercing and tattoos may be risk
factors for viral hepatitis if the tools used, including the ink, are contaminated.
Multiple sexual partners are a risk factor for viral hepatitis.
Alcohol abuse is an important cause of cirrhosis of the liver [47]. Information on
the use of medications or dietary supplements, acutely or chronically, by prescrip-
tion, over the counter, or from health food stores is fundamental in cases of drug-
induced liver injury [48]. The drinking of “bush tea,” a practice carried out in some
countries, has been associated with Budd–Chiari syndrome, which can present dra-
matically with ascites and hepatic insufciency [49]. Contraceptive pills can be
associated with hepatic adenomata and vascular thrombosis [50].
Malignant liver tumors have been associated with exposure to certain compounds
used in industry (e.g., vinyl chloride [51], inorganic arsenical [52], and to aatoxin
B1 [53], which can result from the ingestion of contaminated food products (e.g.,
grains) with the mold Aspergillus avus.
Inquiring about travel to geographic areas where certain conditions are endemic
may reveal diagnostic possibilities. Examples of infectious diseases that may
involve the liver include leptospirosis, malaria, Q fever, amebiasis, and schistoso-
miasis [54].
Recognizing Hepatic Manifestations ofComorbidities
Chronic conditions can be associated with liver involvement, clinical or subclinical.
Heart and liver disease can coexist [55]. Jaundice is not uncommon in patients with
decompensated heart failure [56] and patients with sepsis [57, 58]. Obesity can be
associated with an abnormal serum liver prole, as can diabetes mellitus [59], usu-
ally associated with fatty liver. A patient with amyloidosis may have the liver inl-
trated by amyloid manifested as hepatomegaly [60], and an immunosuppressed
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