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CASE 17: A ROUTINE ‘HEALTH CHECK’ FOR A
55-YEAR-OLD MAN
A 55-year-old man presents to his GP for his annual check-up. He has a history of hyperten-
sion, which is controlled by amlodipine, and hyperlipidaemia, for which he takes a statin. He
does not complain of any particular symptoms, but notes that he has been urinating more
frequently. He wonders whether this may be an early sign of diabetes, as both his brothers
have recently been diagnosed with this condition. He has a family history of cardiovascular
disease, with both his parents having suered a heart attack in their 60s. He recently stopped
smoking but has a 35 pack-year history.
Examination
Body mass index (BMI) is 28. Cardiovascular, respiratory, abdominal and neurologic exami-
nations are unremarkable. Digital rectal examination reveals a small and benign-feeling
prostate.
QUESTIONS
1.
What investigations may be used to diagnose diabetes in this gentleman?
2. Describe the pathophysiology of type 2 diabetes.
3. What are the complications of diabetes, and what do you know about their
aetiology?
4. Discuss the overall principles of management of this patient, assuming he is
found to be diabetic.
DOI: 10.1201/9781003242697-18
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100 Cases in Clinical Pathology and Laboratory Medicine
50
ANSWERS
Type 2 diabetes mellitus is predominantly a disease of the older population and accounts for
90% of cases of diabetes. It may be diagnosed through three tests: (1) fasting glucose levels,
(2) glucose tolerance test and (3) glycated haemoglobin levels. Additionally, in this case, test-
ing the urine for glucose might be useful, though it must be remembered that around 10% of
cases of glycosuria are not caused by hyperglycaemia.
Fasting glucose levels were the easiest way in which to test for diabetes until glycated haemo-
globin (HbA1c) assays became available. The World Health Organization (WHO) criteria
for diabetes require a fasting glucose level of ≥7 mM, since that is the level above which the
microvascular complications of diabetes become detectable. An oral glucose tolerance test
(measuring plasma glucose 2 hours after a standardised glucose load, with levels ≥11.1 mM
being diagnostic of diabetes) is a more sensitive marker of glucose dysregulation but is more
expensive and less reproducible. More recently, the use of HbA1c levels have been used in
diagnosing type 2 diabetes. HbA1c measures the non-enzymatic glycation of amino acids on
the haemoglobin molecule and reflects the glycaemic state over the prior 8–12 weeks. Normal
levels are between 4% and 6%, with the WHO recognising a threshold of 6.5% as the cut-o
point for diagnosing type 2 diabetes.
The two main metabolic defects that underlie type 2 diabetes are insulin resistance and sub-
sequent pancreatic β-cell dysfunction. The former is caused by both quantitative and quali-
tative changes in insulin signalling, such as reduced receptor tyrosine kinase activity, which
is strongly linked to obesity (‘lipotoxicity’). Initially, insulin resistance is compensated for by
pancreatic β-cell hypersecretion of insulin; however, there is eventual decompensation, the
mechanisms of which remain unclear, but are likely linked to lipotoxicity and ‘glucotoxicity’.
It is also important to be aware of the genetic link in type 2 diabetes, which is stronger than
in type 1 diabetes.
Life expectancy in diabetics is reduced by 5–10 years compared to non-diabetics. The major
causes of excess mortality are cardiovascular disease, renal problems and infection. Hence,
the complications of diabetes are just as important to monitor as glycaemic control itself.
Broadly speaking, these complications may be categorised as either microvascular (disease
of small blood vessels) or macrovascular (large-vessel disease). Microvascular complications
include retinopathy, nephropathy and neuropathy, while the predominant macrovascular
complications are cardiovascular, cerebrovascular and peripheral vascular disease.
The principal mechanism underlying macrovascular complications is accelerated athero-
sclerosis of large vessels, leading to a higher risk of thrombosis and occlusion, while the basic
pathophysiology underlying microangiopathy is thickening of capillary basement mem-
branes in the retina, kidneys and vaso nervorum. In the kidney, these thickened capillaries
are more leaky than normal to plasma proteins, giving rise to microalbuminuria. Similarly,
in the eyes, microangiopathy gives rise to non-proliferative or proliferative retinopathy.
Indeed, diabetes is the most common cause of blindness in individuals under 65 years of age.
Given the burden of disease that diabetes imposes, its management is multi-faceted.
Patient education and dietary measures form the basis of conservative management, par-
ticularly in diabetics whose β-cells are able to compensate. Oral anti-diabetic agents that
aim to either stimulate insulin secretion (e.g., sulphonylureas) or increase insulin sensitivity
(e.g., metformin) may be required to optimise glycaemic control, and the last resort is insulin.
However, it is important to remember that diabetes management is not just about control-
ling sugar levels but that hypertension and hyperlipidaemia need to be aggressively managed
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Case 17: A Routine ‘Health Check’ for a 55-Year-Old Man
51
too. Additionally, patients with nephropathy require angiotensin-converting enzyme (ACE)
inhibitors or angiotensin receptor antagonist therapy and regular diabetic eye screening is
needed to monitor for retinopathy.
KEY POINTS
•
Type 2 diabetes is the most common form of diabetes and may be diagnosed via
measurement of fasting glucose levels, an oral glucose tolerance test, or HbA1c
levels.
•
The pathophysiology underlying the disease stems from insulin resistance and
eventual pancreatic β-cell dysfunction and decompensation.
•
Management of type 2 diabetes involves not only aggressive glycaemic control but
also minimising cardiovascular risk factors and possible renal and retinal disease.
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53
CASE 18: COLLAPSE IN A PATIENT UNDERGOING
CHEMOTHERAPY
A 30-year-old man undergoing his first cycle of Adriamycin, bleomycin, vinblastine, dacarba-
zine (ABVD) chemotherapy for bulky stage II Hodgkin’s lymphoma is brought into hospital by
his wife after collapsing at home. His wife says that the patient has been vomiting several times
over the past 24 hours and has been complaining of increased fatigue. Though drowsy, he says
that he has been experiencing numbness in his hands over the past couple of hours as well.
Examination
Physical examination reveals an ill-looking man, with cool peripheries. His vital signs show
T 36.2°C, BP 95/60, HR 100 and regular, RR 24 and 95% O
2
saturation on room air. An
ECG shows peaked T waves and prolongation of the QRS (0.14 ms). A fingerprick glucose is
5.6 mM, and capillary refill time is 3 s. Glasgow Coma Scale (GCS) is 14/15 (E4, V4, M6).
Given his clinical state, the patient is catheterised, and urine output is 10 mL in the first 30
minutes, improving to 25 mL over the next 30 minutes after fluid resuscitation.
INVESTIGATIONS
Haemoglobin 11.9
White cells 5.6
Platelets 180
Sodium 133
Potassium 6.3
Urea 15.9
Creatinine 156
Bilirubin 10
Alanine aminotransferase 25
Aspartate aminotransferase 30
Alkaline phosphatase 110
Corrected calcium 1.65
Phosphate 1.8
International normalised ratio 1.1
QUESTIONS
1. Renal function is grossly deranged in this patient. What are the possible causes
of this, and how may they be differentiated?
2. Given the clinical picture and test results, suggest an underlying aetiology for
this patient’s presentation.
3. Discuss the pathophysiology of the likely underlying diagnosis.
4. What are the main aspects in managing this patient in the acute setting?
DOI: 10.1201/9781003242697-19
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ANSWERS
This patient has acute renal failure, which may be defined as the rapid loss of renal function
with retention of urea, creatinine and other metabolic products and usually characterised by
oliguria. His urea and creatinine levels are around 1.5 times the upper limit of normal, while
his urine output (prior to fluid resuscitation) of 20 mL/hr is significantly less than expected of
an adult male. Classically, the causes of acute renal failure are categorised as:
•
Pre-renal, which arises from hypovolaemia leading to inadequate renal blood flow
(haemorrhage, sepsis, heart failure, diarrhoea and use of diuretics)
•
Intrinsic renal disease, which may aect the glomeruli (e.g., various glomerulo-
nephritides), tubules, and interstitium (e.g., drugs such as non-steroidal anti-inflam-
matory drugs [NSAIDs] and aminoglycosides, contrast media, and intrarenal
obstruction arising from renal calculi or the cast nephropathy in multiple myeloma),
or the blood vessels (e.g., vasculitis, hypertension, diabetes)
•
Post-renal obstruction, which leads to renal failure when both outflow tracts are
obstructed or when one is obstructed in patients with a single kidney (e.g., bladder
outflow obstruction, ureteric calculi, intratubular crystal nephropathy, and urothe-
lial neoplasms)
Measurement of urine composition and using ratios of serum urea:creatinine may help dif-
ferentiate between the above when the history is not especially suggestive, as shown below.
Measure Pre-renal Renal Post-renal
Urine osmolality (mOsm/kg) >500 <350 <350
Urine Na (mM) <10 >20 >40
Fractional excretion of Na (%) <1 >2 >4
Serum Ur:Cr >100:1 <40:1 40–100:1
Here, renal failure is accompanied by hyperkalaemia, hypocalcaemia and hyperphospha-
taemia. These are suggestive of tumour lysis syndrome (TLS) as the underlying aetiology for
the renal failure, with hypovolaemia as a contributory factor too. TLS is classified as either
laboratory TLS or clinical TLS. Laboratory TLS requires the presence of two or more meta-
bolic abnormalities (hyperuricaemia, hyperkalaemia, hypocalcaemia, hyperphosphataemia)
occurring 3 days prior to or up to 7 days after the start of anti-cancer therapy, whereas clini-
cal TLS is present when laboratory TLS is accompanied by the clinical findings of raised
serum creatinine, seizures, arrhythmia, or death. Our patient meets the criteria for both.
TLS is most frequently seen with chemotherapy against rapidly proliferating tumours,
typically haematologic cancers, given their high rate of cell turnover. The pathophysiology
behind TLS is the release of potassium, phosphorus and nucleic acids from rapidly dividing
cancer cells when they begin to be lysed by anti-cancer therapy. Hyperphosphataemia gives
rise to hypocalcaemia, and nucleic acids are metabolised to uric acid, producing hyperuri-
caemia. Renal failure may arise since both urate and phosphate can crystallise and cause
intratubular obstruction. Crystal-independent mechanisms, including renal vasoconstriction
and reduced renal blood flow, may also have a part to play. In this case, we see the manifes-
tations of these metabolic abnormalities, with ECG changes suggestive of hyperkalaemia,
paraesthesia probably induced by hypocalcaemia, and oliguria indicative of renal failure.
Given the patient’s hypovolaemic state, which predisposes the patient to develop renal failure,
the immediate management priority is fluid resuscitation. Hydration also helps minimise aci-
dosis and increases urine pH, which reduces the risk of urate crystallisation. Hyperkalaemia
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Case 18: Collapse in a Patient Undergoing Chemotherapy
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requires intervention with calcium gluconate, insulin and dextrose, given that ECG changes
are seen with the higher risk of arrhythmia. The other metabolic abnormality that requires
urgent intervention is hyperuricaemia. Rasburicase, which converts uric acid to the inactive
and soluble metabolite allantoin, may be preferred to xanthine oxidase inhibitors such as
allopurinol, as rasburicase also breaks down existing uric acid, whereas allopurinol only pre-
vents its further formation. Clinical TLS patients also often require management in an ITU
setting, given the need for cardiac monitoring and supportive management of renal failure
through haemofiltration.
KEY POINTS
•
Acute renal failure is the rapid loss of renal function with retention of waste metab-
olites such as urea and creatinine and may be due to pre-renal, renal, or post-renal
causes.
•
TLS occurs with rapid lysis of rapidly proliferating cancer cells after anti-cancer
therapy and produces several metabolic derangements, including hyperphospha-
taemia, hyperkalaemia and hyperuricaemia.
•
Crystallisation of phosphate and urate may occlude renal tubules, causing renal
failure.
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57
CASE 19: A 10-DAY-OLD BABY WITH AMBIGUOUS
GENITALIA
A 24-year-old refugee brings her 10-day-old child to hospital after finding the child less
responsive than normal, not feeding appropriately and vomiting several times for the past few
days. The baby was delivered vaginally at term by the child’s aunt, and the mother received
no pre- or post-natal care.
Examination
Examination reveals an ill-looking neonate with evidence of dehydration (HR 180, BP 65/30,
CRT 3 s, sunken fontanelles). There are no rashes. On unclothing the child and examining
the external genitalia, a phallic-appearing structure is noted and there is fusion of the skin
folds surrounding it. No testes are palpated, and the physician is uncertain about the sex of
the neonate.
INVESTIGATIONS
Haemoglobin 17
Haematocrit 55%
White cells 14
Sodium 135
Potassium 6.2
Urea 19.5
Creatinine 65
ABG (on room air):
pH 7.28
QUESTIONS
1. What are the possible causes of ambiguous genitalia? What are the basic prin-
ciples of evaluating this condition?
2. What is the likely diagnosis in this case and why?
3. What treatment does this baby now require?
DOI: 10.1201/9781003242697-20
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100 Cases in Clinical Pathology and Laboratory Medicine
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ANSWERS
Around 1 in 4500 newborns have what may be considered ‘ambiguous genitalia’. Broadly,
there are two causal categories of ambiguous genitalia:
1. Virilised XX female. This may be the result of androgens of fetal origin (e.g., con-
genital adrenal hyperplasia [CAH]) or maternal (e.g., drugs such as progesterone
and danazol, maternal androgen-secreting tumours of the ovary or adrenal gland).
The other main causes are dysmorphic conditions such as Beckwith-Wiedemann
and Seckel syndromes.
2. Undervirilised XY male. This may arise from a biosynthetic defect leading to
reduced fetal androgen production (e.g., Leydig cell defects, 5-α-reductase defi-
ciency, deficiency of anti-Mullerian hormone), end-organ unresponsiveness to
androgens (androgen insensitivity syndrome), dysmorphic syndromes (e.g., Smith-
Lemli-Opitz syndrome) and testicular dysgenesis or malfunction.
The evaluation of ambiguous genitalia should begin with the history to look for the use of
any drugs that may cause female virilisation, any evidence of maternal virilisation that may
suggest a maternal androgen-secreting tumour, and any family history of a genetic disorder.
A complete examination of the child is required to assess its general condition, identify dys-
morphic features, and assess the external genitalia (number of gonads, degree of virilisation,
length of the phallus and any hyperpigmentation that would suggest excessive adrenocorti-
cotropic hormone [ACTH] production). The most important initial tests are to determine
karyotype and assess internal anatomy by way of pelvic ultrasound. The other priority is
to avoid a salt-losing crisis (seen in CAH); therefore, blood tests for electrolytes, luteinising
hormone (LH), follicle-stimulating hormone (FSH) and androgen levels (testosterone, dehy-
droepiandrosterone [DHEA], androstenedione and 17-OH-progestrone) are required.
In this neonate, physical examination is consistent with clitoromegaly and labial fusion, sug-
gesting a virilised XX female, though formal karyotypical analysis is needed for confirma-
tion. The blood tests are informative of the diagnosis, as they reveal mild hyponatraemia,
hyperkalaemia, evidence of hypovolaemia and acidosis. These are consistent with the salt-
wasting form of 21-hydroxylase deficiency, the enzyme defect accounting for more than 90%
of cases of CAH.
CAH is an autosomal recessive condition caused by deficiencies of one of five enzymes
required for adrenal steroid synthesis (see Figure 19.1). 21-Hydroxylase is required for the
synthesis of aldosterone and cortisol but not that of adrenal androgens. Deficiency of cortisol
leads to feedback upregulation of ACTH, which overstimulates the adrenal cortex, produc-
ing adrenal hyperplasia. Since a block in adrenal mineralocorticoid and glucocorticoid pro-
duction is present, the steroid precursors are diverted towards the androgen pathway, leading
to their overproduction and subsequent virilisation. The aldosterone and cortisol deficiency
leads to a state of adrenal insuciency, causing hyponatraemia, hyperkalaemia, acidosis and
circulatory collapse (typically between days 5 and 15).
This case illustrates the severest form of 21-hydroxylase deficiency, the so-called ‘salt-wasting’
subtype, where there is total lack of the enzyme. Partial enzyme deficiency produces a less
severe phenotype (‘simple virilising’) with adequate aldosterone production, and hence no
fluid or electrolyte losses, but still with a strong virilising eect. Non-classic 21-hydroxylase
deficiency is more common than classic forms of the disease and produces late-onset and
mild clinical symptoms (e.g., premature puberty, tall stature, hirsutism, oligomenorrhoea),
usually without gross virilisation at birth.
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