Glucose-6-phosphate dehydrogenase deficiency is an X-linked recessive disorder in which there is a deficiency of the enzyme G6PD. This causes instability of red blood cell membranes under oxidative stress leading to haemolysis.

Triggers include:
1) Fava beans
2) Sulphonamides
3) Primaquine
4) Anti-TB drugs
5) Infections

Most individuals will be asymptomatic until exposed to one of the triggers listed above. It is the commonest human enzyme defect and affects males more than females because of the X-linked inheritance pattern. The use of penicillins and cephalosporins is generally safe.

Deficiency of Factor IX causes Haemophilia B, and like the other Haemophilia’s, it has an X-linked recessive pattern of inheritance, affecting males born to carrier mothers.

Haemophilia B is the second commonest form of haemophilia and is rarer than haemophilia A. Haemophilia B is similar to haemophilia A but is less severe. You can distinguish the two disorders by specific coagulation factor assays.

The incidence of Haemophilia B is one-fifth of that of haemophilia A.

In laboratory findings, you get prolonged APTT, normal PT and low factor IX for Haemophilia B.

There is also a variation called Leyden, in which factor IX levels are below 1% until puberty, when they rise, potentially reaching as high as 40-60% of normal. This is thought to be due to the effects of testosterone at puberty.

The clinical and laboratory findings, in this case, support a diagnosis of polycythaemia vera. A plethoric appearance, lethargy, splenomegaly and itching are common in this disease. Patients may also have gouty arthritis, Budd-Chiari syndrome, erythromelalgia, stroke, myocardial infarction or DVT. The average age for diagnosis of Polycythaemia Vera is 65-74 years. It is a haematological malignancy in which there is overproduction of all three cell lines. Venesection is the treatment of choice as it would cause a decrease in the number of red blood cells within the body.

Erythropoietin is given in patients with chronic renal failure as they lack this hormone. Administration of erythropoietin in such patients causes stimulation of the bone marrow to produce red blood cells.

Desferrioxamine is a chelating agent for iron and is given to patients with iron overload due to repeated blood transfusions, e.g. in thalassemia patients.

Penicillamine is a chelating agent for Copper, given as treatment in Wilson’s disease.

Features of sickle cell disease include:
Anaemia (symptoms are usually mild because the O2 dissociation curve of Hb S is shifted to the right)
Vaso-occlusive crisis
Visceral sequestration crisis
Aplastic crisisIncreased susceptibility to infection
Other clinical features: Pigment gallstones with cholecystitis
Chronic leg ulcers
Avascular necrosis of the femoral and humeral heads or other bones
Cardiomyopathy
Pulmonary hypertension
Proliferative retinopathy
Priapism
Renal papillary necrosis
Stroke

Raised platelet levels have emerged as a cancer risk marker, according to a large population-based study published in 2017(link is external). According to the study, 12 percent of men and 6% of women with thrombocytosis were diagnosed with cancer within a year. These figures increased to 18% in men and 10% in women if a second platelet count was taken within 6 months of the first and showed an increased or stable elevated platelet count.

The researchers discovered that thrombocytosis linked to cancer is most common in colorectal and lung cancers, and it is linked to a worse prognosis. Furthermore, one-third of the cancer patients in the study had no other symptoms that would have prompted an immediate cancer referral.

The exact mechanism by which these cancers cause thrombocytosis is unknown, but one theory proposes the existence of pathogenic feedback loops between malignant cells and platelets, with a reciprocal interaction between tumour growth and metastasis, as well as thrombocytosis and platelet activation. Another hypothesis is that thrombocytosis occurs independently of cancer but aids in its spread and progression.

The findings show that routinely testing for thrombocytosis could cut the time it takes to diagnose colorectal and lung cancer by at least two months. In the UK, this could result in around 5500 earlier cancer diagnoses per year.

Because the positive predictive value of thrombocytosis in middle age for cancer (10%) is higher than the positive predictive value for a woman in her 50s presenting with a new breast lump (8.5%), this is clearly an important research paper that should be used to adjust future clinical practise. The current NICE guidelines predate these new research findings, so we’ll have to wait and see how they affect cancer referral guidelines in the UK.

Because there are so many possible cancers associated with thrombocytosis, the treating clinician should take a thorough history and perform a thorough clinical examination if a patient is diagnosed with it. Further investigation and the most appropriate referral route should be aided by this information.

It’s worth noting that the patients in the study had their blood tests done for a medical reason rather than as a random screening test.

If there are no other symptoms to guide investigation and referral (one-third of the patients in the study had no other symptoms), keep in mind that the two most common cancers encountered were colorectal and lung cancer, so a chest X-ray and a faecal immunochemical test (FIT) for faecal blood may be reasonable initial investigations.

All the Haemophilia’s have an X-linked recessive inheritance pattern, so they only manifest in male patients. Diseases with a mitochondrial inheritance pattern include MELAS syndrome, Leigh syndrome, LHON and MERRF syndrome. Autosomal dominant disorders include Huntingdon disease and Marfan syndrome. X-linked dominant diseases include Fragile X syndrome. Autosomal recessive diseases include cystic fibrosis and sickle cell disease.

The most common type of adult leukaemia is chronic lymphocytic leukaemia (CLL). It develops as a result of relatively mature lymphocytes clonally proliferating. The B-cell lineage accounts for approximately 95% of cases. CLL is primarily a disease of adult men, with men over the age of 50 accounting for more than 75% of CLL patients.

It is the most indolent form of chronic leukaemia, and it is frequently discovered by chance when blood counts are taken for other reasons, such as ‘well man’ screening tests. The patient may develop lymphadenopathy, hepatosplenomegaly, anaemia, and infections as the disease progresses.

The following are examples of CLL laboratory findings:
Clonal B cell lymphocytosis (diagnosed at greater than 5 x 109/l, but can reach 300 x 109/l)
In advanced disease, normocytic, normochromic anaemia is present.

Patients with autoimmune-related haemolytic anaemias have a positive direct antiglobulin test (DAT).

Although bone marrow aspiration is not always required, it can aid in the diagnosis of CLL. If there has been rapid lymph node enlargement, a lymph node biopsy is required to rule out Richter’s syndrome. This is the transition from low-grade lymphoma to high-grade lymphoma, which is characterised by fever, weight loss, and pain.

Although there is no cure for CLL, it can be managed with chemotherapy regimens that help patients live longer. Early treatment has no benefit, and the standard treatment for early disease is to watch and wait, with examinations and blood counts every 3 to 12 months. Chemotherapy is usually reserved for patients who have a disease that is active and causing symptoms.

The following is the overall prognosis for CLL:
1/3 will not require treatment and will live a long time.
1/3 will go through an indolent phase before the disease progresses.
1/3 of patients will have an aggressive disease that requires immediate treatment.

Features include:
– severe anaemia (becoming apparent at 3 – 6 months when the switch from gamma-chain to beta-chain production takes place)
– failure to thrive
– hepatosplenomegaly (due to excessive red cell destruction, extramedullary haemopoiesis and later due to transfusion related iron overload)
– expansion of bones (due to marrow hyperplasia, resulting in bossing of the skull and cortical thinning with tendency to fracture)
– increased susceptibility to infections (due to anaemia, iron overload, transfusion and splenectomy)
– osteoporosis
– hyperbilirubinaemia and gallstones
– hyperuricaemia and gout
– other features of haemolytic anaemia
– liver damage and other features of iron overload

Megaloblastic anaemia occurs when there is inhibition of DNA synthesis as red blood cells are produced. Impairment of DNA synthesis causes the cell cycle to be unable to progress from the growth stage to the mitosis stage. As a result, there is continuous cell growth without division, with an increase in mean corpuscular volume (MCV), which presents as macrocytosis. The most common cause of this defect in red cell DNA synthesis is hypovitaminosis, in particular, vitamin B12 deficiency or folate deficiency.
Folate is an essential vitamin that can be found in most foods, and is highest in liver, green vegetables and yeast. 200 – 250 μg is found in the normal daily diet, and about 50% is absorbed. The daily adult requirement is about 100 μg and its absorption is principally from the duodenum and jejunum. Folate stores are normally only adequate for 4 months and so clinical features of folate deficiency usually become evident after this time.

Multiple myeloma is a clonal abnormality affecting plasma cells in which there is an overproduction of functionless immunoglobulins. The most common patient complaint is bone pain, especially in the back and ribs. Anaemia and renal failure are common, along with hypercalcemia. Hypercalcemia may lead to an altered mental status, as in this case.

Chronic lymphocytic leukaemia occurs due to the overproduction of lymphocytes, usually B cells. CLL may present with an asymptomatic elevation of B cells. Patients are generally more than 50 years old and present with non-specific fatigue and weight loss symptoms.

There is no history of alcohol abuse in this case. Furthermore, patients with a history of alcohol abuse may have signs of liver failure, which are not present here.

Metastatic prostate cancer would most often cause lower backache as it metastasises first to the lumbar spine via the vertebral venous plexus.

A patient with Vitamin B12 deficiency would have anaemia, megaloblastic, hypersegmented neutrophils, and signs of peripheral neuropathy.