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69
CASE 24: A YOUNG MAN WITH ‘HIGH
CHOLESTEROL’
A 38-year-old man is advised to see his GP by his new private health insurer, as his baseline
blood tests showed that he had “too much cholesterol in his body”. He does not suer from
any active medical problems. His father died suddenly at age 53 of an unclear cause, and his
two brothers developed type 2 diabetes in their 40s. He is an ex-smoker with a 10 pack-year
his tory.
Examination
General examination reveals an overweight man (body mass index [BMI] 28), with presence
of a bilateral corneal arcus. Blood pressure is 135/75. The rest of the examination is unre-
markable except for the presence of tendon xanthomas on his hands.
INVESTIGATIONS
FBC Normal
U+E Normal
LFT Normal
Fasting bloods:
Total serum cholesterol 8 mM
LDL cholesterol 5 mM
HDL cholesterol 1.5 mM
Triglyceride 1.2 mM
QUESTIONS
1. Give a brief account of lipid metabolism.
2. What are the causes of hyperlipidaemia? Which cause is the most likely in this
ca se?
3. What is the pathophysiology underlying the most likely cause, and what are sug-
gestive treatment options for this patient?
DOI: 10.1201/9781003242697-25
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100 Cases in Clinical Pathology and Laboratory Medicine
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ANSWERS
The principal lipids in plasma are fatty acids, triglycerides (TGs), and cholesterol. These
are transported in plasma in association with proteins, with free fatty acids carried by albu-
min and other lipids circulating in complexes, termed lipoproteins, that have a non-polar lipid
core and a surface layer of phospholipids, cholesterol and apolipoproteins. Lipoproteins are
classified based on their density, increasing from chylomicrons to very low-density lipopro-
teins (VLDLs), intermediate-density lipoproteins (IDLs), low-density lipoproteins (LDLs) and
high-density lipoproteins (HDLs). As density increases, less TG is present, with increasing
amounts of cholesterol and proteins.
Chylomicrons are formed from dietary fat, and their function is to transport TG to the tis-
sues. VLDLs are the primary transport mode for endogenous TG, and as TGs are released
to tissues by the action of lipoprotein lipase, they become denser to form IDL and then LDL.
LDL carries the majority of plasma cholesterol, which may be taken up by macrophages, a
pathogenic event of atherosclerosis. LDL also binds to receptors in the liver, with subsequent
lysosomal degradation leading to release of cholesterol intracellularly, which is excreted into
bile. The metabolism of HDL is complex, but essentially it mediates ‘reverse cholesterol
transport’ by taking up cholesterol from senescent cells and transferring it to remnant lipo-
protein particles that are eventually cleared by the liver.
Hyperlipidaemia is one of the key modifiable risk factors for the development of atheroscle-
rosis. It may either be primary, arising from a genetic disorder, or secondary to other condi-
tions, including hypothyroidism, diabetes mellitus, obesity, nephrotic syndrome, renal and
liver failure, drugs (e.g., thiazides, antiretrovirals) and alcohol.
In this case, the man has high levels of total and LDL cholesterol. Given his young age,
potential family history, and the clinical findings of tendon xanthomata and corneal arcus, a
primary hyperlipidaemia is likely to account for this. The likely diagnosis is familial hyper-
cholesterolaemia (FH), which is an autosomal dominant disorder of LDL metabolism, usu-
ally arising from mutations in the LDL receptor leading to reduced uptake by the liver.
The homozygous form of the disease is rare and presents in childhood; our patient is more
likely to have the heterozygous form, which is reasonably common, with a prevalence of
approximately 1 in 500. It typically presents in adulthood with total cholesterol >7.5 and
LDL cholesterol >5; a family history of early coronary artery disease or hypercholesterolae-
mia in a close relative is also required to make the diagnosis. Tendon xanthomas, which are
essentially deposits of cholesterol, are pathognomonic.
The management of FH involves lifestyle changes (dietary restriction and regular exercise)
and medications, principally using statins, ezetimibe (which inhibits intestinal cholesterol
absorption), bile acid sequestrants and the newer PCSK9 inhibitors.
KEY POINTS
•
LDL is the principal lipoprotein responsible for transporting cholesterol in the
body and is cleared by the liver, with excretion of cholesterol in bile.
•
Mutations in the LDL receptor cause FH, which presents with hyperlipidaemia,
hypercholesterolaemia, early-onset vascular disease and tendon xanthomas.
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71
CASE 25: RASH AFTER A BONE MARROW
TRANSPLANT
A 45-year-old man presents to the haemato-oncology clinic with a rash. He was diagnosed
with acute myeloid leukaemia a year ago and received an allogeneic bone marrow transplant
for relapsed disease 28 days ago. He also complains of abdominal pain and worsening vomit-
ing and diarrhoea. He is taking cyclosporin.
Examination
The patient has a fever of 38.3°C. There are confluent faint, erythematous, blanching mac-
ules with indistinct borders involving the palm and dorsum of both hands, with sparing of
the metacarpophalangeal and proximal interphalangeal joints. There are also perifollicular
erythematous macules on the upper trunk. There is prominent desquamation, and rubbing
the skin results in exfoliation.
General examination reveals scleral icterus. His cardiorespiratory examination is unremark-
able. He is tender in the epigastrium and right upper quadrant.
INVESTIGATIONS
Blood tests are taken, but the results are pending.
QUESTIONS
1.
Based on the clinical findings, suggest a differential diagnosis.
2. Discuss the pathophysiology of the likely diagnosis.
3. What investigations are required?
4. Outline the principles of treatment in this case.
DOI: 10.1201/9781003242697-26
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ANSWERS
After a bone marrow transplant (and any associated chemotherapy), the main risks are infec-
tion (from low white cell counts and the use of immunosuppressants, such as cyclosporin),
bleeding (from low platelet counts) and graft-versus-host disease (GVHD). The causes of a
rash in this setting can be a viral, bacterial or drug exanthem; GVHD; or toxic epidermal
necrolysis. Given that this patient also has a fever, diarrhoea, vomiting, abdominal pain and
signs of jaundice, he may also have an underlying gastroenteritis or liver pathology.
An erythematous rash that develops on the palms or soles of the feet of a patient 10–30 days
after a bone marrow transplant is characteristic of GVHD. The pathophysiology of GVHD
is still not completely understood, but three requirements for it to occur are proposed:
1. The graft contains immune cells (T cells).
2. The host expresses antigens that are dierent from those in the donor.
3. The host is unable to mount an immune response to eliminate the donor cells.
Essentially, donor T cells recognise host antigens as foreign or ‘non-self’ and provoke an
immune response also involving B cells and leading to production of inflammatory cytokines
such as tumour necrosis factor alpha (TNF-α) and interleukin (IL)-1. As the patient’s immune
system is designed to be suppressed to allow engraftment of the recipient bone marrow, this
response is directed against the patient’s own body.
GVHD is a potentially life-threatening problem that can occur in up to 80% of successful
allogeneic bone marrow transplants. It may also occur in a milder form in up to 10% of
autologous engraftments, where it is hypothesised that chemotherapy exposes self-antigens,
which the immune system did not recognise before.
Clinically, GVHD manifests like an autoimmune disease with a macular-papular rash, jaun-
dice, hepatosplenomegaly, and ultimately organ fibrosis. It classically involves the skin, gas-
trointestinal tract, and the liver. Further investigations in this patient would include a full
blood count, measurement of renal function and electrolytes and liver function tests. A skin
biopsy would allow histological grading and assessment of the severity of the disease.
Depending on severity, treatment of acute GVHD may involve topical and intravenous ste-
roid therapy, immunosuppression (e.g., cyclosporine), or biologic therapies targeting TNF-α
(e.g., infliximab, etanercept), a key inflammatory cytokine. Resolution often takes more than
1 month, and patients should be carefully monitored for opportunistic infections.
Prognosis is related to response to treatment. The mortality of patients who completely respond
can still be around 20%, and the mortality in those who do not respond is as high as 75%.
KEY POINTS
•
The complications of a bone marrow transplant include infection, bleeding and
GVHD.
•
Fever and a rash in a patient who recently received chemotherapy or is using an
immunosuppressant should be investigated thoroughly and has a broad differen-
tial diagnosis.
•
GVHD is a type IV, T-cell–mediated hypersensitivity reaction by the graft against
the host.
•
GVHD is potentially life-threatening and is more common in allogeneic bone mar-
row transplants.
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73
CASE 26: A FALL ON AN OUTSTRETCHED HAND
A 55-year-old woman presents to the emergency department after slipping on an icy road
and falling on her outstretched right hand. She complains of pain in her right wrist that has
not responded to simple analgesia and has been unable to use her right hand since falling.
She has a history of polymyalgia rheumatica, though has not had a flare-up for a couple of
years. She is a non-smoker.
Examination
The patient is haemodynamically stable. She is tender on palpation of the right wrist joint
and the ulnar styloid. There is no evidence of any neurovascular compromise.
INVESTIGATIONS
Plain radiograph of the wrist: transverse fracture of the distal radius with minimal dorsal
displacement of the wrist; there is also a fracture of the ulnar styloid.
The fracture is reduced; a back-slab is applied, and the patient is told to return to the
fracture clinic in 2 weeks.
QUESTIONS
1.
What is the name given to this fracture, and what suspicion should its occurrence
raise?
2. What investigations should be arranged in clinic and why?
3. Does the patient require any treatment, and what are the various options in
management?
DOI: 10.1201/9781003242697-27
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ANSWERS
A fracture of the distal radius with dorsal displacement of the distal fragment describes a
Colles fracture, and is classically caused by a fall on the outstretched (extended) hand. The
presence of a Colles fracture, especially in a relatively young individual, should raise the
question of osteoporosis, since it is one of the three ‘fragility fractures’ associated with this
condition (the other two being a fracture of the neck of the femur and vertebral body fracture).
Osteoporosis is characterised by reduced bone mass and microarchitectural disruption with
a resultant reduction in bone strength and predisposition to fracture. It is defined by a reduc-
tion in bone density of 2.5 times or greater from the standard deviation of a young adult
reference mean (i.e. T score ≤ −2.5). Bone density is governed by the rates of bone formation
and breakdown: bone mass accrues through adolescence and reaches a peak in early adult-
hood, remaining relatively stable until around the fourth decade. Beyond this age, bone mass
declines as a result of increased osteoclastic and reduced osteoblastic activity and does so at a
faster rate in women as a result of oestrogen deficiency (oestrogen inhibits osteoclasts).
Osteoporosis may therefore be “primary” (post-menopausal in women) or secondary to an
underlying condition that accelerates the above process. Secondary causes are:
•
Endocrine (e.g., thyrotoxicosis, glucocorticoid excess, hyperparathyroidism)
•
Nutritional (e.g., vitamin D deficiency, malabsorptive conditions such as coeliac
disease)
•
Drugs (principally steroid use)
•
Other (e.g., multiple myeloma, osteogenesis imperfecta, rheumatoid arthritis)
In this case, the underlying aetiology may be a combination of chronic steroid treatment
for polymyalgia rheumatica and post-menopausal oestrogen deficiency. However, routine
investigations to exclude other secondary causes would be worth performing, including a
full blood count and ESR (to identify chronic inflammatory conditions such as rheumatoid
arthritis), bone profile (for Paget’s disease), liver and renal function (vitamin D deficiency
in renal failure), thyroid function and a screen for myeloma (Bence Jones proteinuria and
serum immunoglobulins). The other important test would be to perform a dual-energy x-ray
absorptiometry (DEXA) scan that will be able to measure bone density and confirm the
diagnosis.
Treatment of osteoporosis is via a combination of lifestyle and pharmacologic measures. The
former includes fall education and prevention, as well as dietary supplementation of cal-
cium and vitamin D. Pharmacologic measures consist of anti-resorptive agents (e.g., bisphos-
phonates, which inhibit osteoclasts; hormone replacement therapy; and selective oestrogen
receptor modulators [SERMs] such as raloxifene) and anabolic agents (e.g., strontium and
parathyroid hormone–related peptides such as teriparatide). In this patient, a bisphospho-
nate would certainly be indicated, given that a fragility fracture has already occurred.
KEY POINTS
•
Fragility fractures include fractures of the distal radius (Colles fracture), neck of
the femur, and vertebral body.
•
Osteoporosis is characterised by a reduction in bone mass and most commonly
arises as an age-related phenomenon in women.
•
Treatment for osteoporosis usually involves the use of bisphosphonates, which
inhibit osteoclastic activity.
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75
CASE 27: A PATIENT IN FOLLOW-UP AFTER A
LIVER TRANSPLANT
A 48-year-old gentleman with a history of alcoholic liver disease undergoes an orthotopic
liver transplant. The surgery goes well, and the patient has a reasonably uneventful post-
operative course. He returns to the transplant clinic 4 weeks later for routine follow-up. He
says he has been feeling tired and has not yet returned to work. His wife has noticed that his
eyes have turned slightly yellow.
Examination
General examination reveals scleral icterus. Abdominal examination reveals a healed
‘Mercedes-Benz’ scar in the right upper quadrant. There is no organomegaly or palpable mass.
INVESTIGATIONS
Haemoglobin 12.0
White cell count 5
Platelets 302
Mean cell volume 105
Bilirubin 48
Alanine aminotransferase 185
Alkaline phosphatase 540
International normalised ratio 1.4
QUESTIONS
1. What features would indicate that the transplant is being rejected?
2. What are the immunological mechanisms of graft rejection?
3. How can the risk of graft rejection be reduced?
DOI: 10.1201/9781003242697-28
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100 Cases in Clinical Pathology and Laboratory Medicine
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ANSWERS
The leading indication for a liver transplant is alcoholic cirrhosis in adults and biliary atresia
in children. To enhance the viability of the graft, transplants of the liver should take place less
than 24 hours after the harvest. During this time the organ is kept at 4°C and in a specialised
University of Wisconsin preservative solution that facilitates immediate graft perfusion after
transplant. The overall 1-year survival of a liver transplant is over 90%, with 10-year survival
of around 70%.
Allograft transplant rejection tends to involve the biliary epithelium before the vascular endo-
thelium. Thus, the signs of rejection include increased serum bilirubin (indicating reduced
drainage of bile) and deranged liver function tests. If there is suspicion of rejection, other
complications of transplantation must be ruled out. These include operative complications
(e.g., thrombosis or anastomotic leak) and complications of immunosuppression (infection,
especially cytomegalovirus [CMV]) and lymphoproliferative diseases such as Epstein-Barr
virus (EBV)–mediated B-cell proliferation. Diagnosis of CMV infection or EBV B-cell pro-
liferation will often require tissue biopsy of the donated organ.
Transplant rejection can be classified by time course, which relates to the underlying immune
mechanism:
•
Hyperacute organ rejection occurs within minutes of the graft perfusion in the operating
theatre. It is characterised by a type II antibody-mediated hypersensitivity reaction
whereby pre-existing anti-graft antibodies in the recipient bind to foreign antigens.
This results in opsonisation with phagocytes engulfing cells that have been marked
by antibodies. The antibodies activate complement, which enhances phagocytosis
and causes cell lysis. The treatment for hyperacute rejection is immediate removal
of the graft.
•
Acute organ rejection take place a number of weeks after the transplant and is the likely
mechanism in this case. It is characterised by cell-mediated toxicity by cytotoxic T
cells. This process involves host CD4 T cells recognising foreign antigens (on the
graft) and producing cytokines such as interleukin (IL)-2 that stimulate cytotoxic
T cells, which are able to initiate apoptosis of the foreign tissue. The treatment for
acute rejection includes high-dose steroids.
•
Chronic organ rejection can take place months to years after the transplant. It is irre-
versible and characterised by both cell-mediated (cytotoxic T cell) and antibody-
mediated (humoral) immune reactions that result in fibrosis and obliteration of the
blood vessels of the transplanted organ. As it is irreversible, treatment for chronic
rejection is dicult and may include re-transplantation.
All recipients of an organ transplant receive immunosuppressive therapy. This is usually
a triple regimen consisting of corticosteroids, azathioprine and cyclosporin or tacrolimus.
Triple therapy enables the use of lower doses of each drug, thereby reducing side eects.
Corticosteroids downregulate the immune response by inhibiting the principal pro-inflam-
matory transcription factor, NFκB. Azathioprine is a prodrug that is cleaved into the active
metabolite mercaptopurine, which inhibits DNA replication and therefore hinders lympho-
cyte production and replication. Cyclosporin and tacrolimus (the latter is more potent) both
inhibit the protein calcineurin and the production of IL-2 by helper T cells. This results in
reduced activation of helper and cytotoxic T cells.
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Case 27: A Patient in Follow-up after a Liver Transplant
77
KEY POINTS
•
Allograft transplant rejection involves the biliary epithelium before the vascular
endothelium.
•
Other complications of transplantation must be ruled out as a differential diagno-
sis of organ rejection. These include operative complications, infection (especially
by CMV), and EBV-mediated B-cell proliferation.
•
Hyperacute organ rejection is characterised by a type 2 antibody-mediated hyper-
sensitivity reaction whereby antigraft antibodies in the recipient bind to foreign
antigens.
•
Acute organ rejection is characterised by cell-mediated toxicity by cytotoxic
Tcells.
•
Chronic organ rejection is irreversible and characterised by both cell-mediated
(cytotoxic T cell) and antibody-mediated (humoral) immune reactions.
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