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Q1: How would you describe these skin lesions? What is the differential diagnoses?
Figure 1 (see p 430) shows confluent ecchymosis in the background of icteric skin, mainly involving the left thigh. The differential diagnoses of non-palpable purpura/ecchymosis include primary skin conditions (trauma, solar purpura, steroid purpura, capillaritis, and lividoid vasculitis), clotting disorders (thrombocytopenia, clotting factor deficiency, abnormal platelet function), conditions characterised by vascular fragility (amyloidosis, Ehlers-Danlos syndrome, and scurvy), conditions such as monoclonal cryoglobulinaemia, warfarin therapy, cholesterol and fat embolism, autoerythrocytic sensitivity, and Waldenstrom’s macroglobulinaemia.1
Q2: What is the most likely cause of this patient’s skin lesions and thigh abnormality? What features of the skin lesion (fig 1, inset; see p 430) suggests this diagnosis? How will you confirm the diagnosis?
The principal diagnosis to consider in this patient is scurvy (vitamin C deficiency). As is evident, the haemorrhagic lesions are perifollicular, with hyperkeratotic papules (fig 1, inset; see p 430). This patient had mild thrombocytopenia and a mildly prolonged INR, neither of which is likely to produce ecchymosis and haematoma in a single anatomic area in the absence of significant local trauma. As laboratory testing suggested cholestasis, this patient received empirical vitamin K injections (10 mg) subcutaneously for three days, but without clinical improvement. Indeed, spontaneous bleeding into thigh muscle is rare, even in patients with INR values >2.0, such as those on therapeutic anticoagulation with warfarin (coumadin). Sreenivas et al reported two patients on warfarin who had spontaneous iliopsoas haematomas resulting in compressive femoral neuropathy,2 as have others, but this patient did not have evidence of iliopsoas bleeding on computed tomography of the abdomen.
Follicular hyperkeratosis and perifollicular haemorrhages are such a distinctive occurrence in scurvy that they are almost pathognomonic.3 Also, scurvy skin lesions tend to preferentially involve the legs. The various clinical and radiological manifestations of scurvy are listed in box 1. A useful aide memoire about scurvy manifestations is to remember “the four Hs”—namely, haemorrhage, hyperkeratosis, hypochondriasis, and haematological manifestations.4 The diagnosis of scurvy needs a high index of clinical suspicion. It is facilitated by obtaining a good dietary history and is confirmed by plasma and leucocyte ascorbic acid levels. This patient had erratic food habits, and his diet did not include fresh fruits/fruit juices and vegetables. His plasma ascorbate level was 5.68 μmol/l (laboratory normal range 23–57 μmol/l). In eumetabolic individuals, plasma ascorbate levels should be more than 35.2 μmol/l. The normal body pool of ascorbic acid is about 1500 mg (85 mmol) and 3% of this body pool turns over each day, resulting in a half life of about 18 days.1 Scorbutic manifestations tend to occur at levels below 300 mg (17 mmol).1,3 Whole body ascorbate level estimation is impractical, and hence the need for plasma and leucocyte ascorbate levels. Plasma values are affected by recent dietary intake, while leucocyte levels, which changes more slowly, better indicate tissue and total body content.3 Ascorbic acid (C6H6O8), a ketolactone with a molecular weight of 176.1, is required for the peptidyl hydroxylation of procollagen, and its deficiency results in abnormal and unstable triple helical structure of collagen.4 This leads to defective perivascular supportive tissues resulting in capillary fragility and poor wound healing. Ascorbic acid is synthesised by most animals from glucoronic or galactonic acid, which in turn are synthesised from glucose.4 Only a few species, including humans, non-human primates, the Indian fruit bat, monkeys, several species of bulbuls, and guinea pigs lack the enzyme system required for the production of L-ascorbate from glucose. In these species, ascorbic acid must be obtained from exogenous sources.3,4
Box 1: Manifestations of scurvy*
Constitutional: lassitude, diminished appetite and fatigue. Perifollicular skin haemorrhage and hyperkeratosis, splinter haemorrhages of nails.
Hair abnormalities: alopecia; “swan neck” deformity—hair bent in many places; “corkscrew” deformity—coiled, fractured hair.
Red, smooth, shiny, and swollen gums: especially the interdental and marginal gingivae.
Haemorrhage: into muscles and soft tissues (swelling, myalgia, pseudoparalysis); into subperiosteal bone (bone pain) and, rarely, fractures; in the eye—subconjunctival, periorbital, and intraretinal haemorrhages; gastrointestinal bleeding.
Haematological: anaemia (normocytic and normochromic, can be macrocytic and/or megaloblastic in 20% cases); leucopenia and thrombocytopenia rarely; reticulocytosis and reduced haptoglobulin levels.
Others: irritability and cognitive impairment; dyspnoea and cardiac failure in severe deficiency states.
Radiographic changes (children and adults): onset six months to two years; earliest signs in knees; osteoporosis, loss of epiphyseal density with a pencil thin cortex (Wimberger sign), dense zone of provisional calcification (excess osteoid calcification), metaphyseal lucency (Trummerfeld zone), metaphyseal corner fractures (pelkan spurs), and periosteal reaction due to subperiosteal haemorrhage.
* Adapted from references 1, 3 , 4, and 5.
Q3: How is this condition treated?
Very small quantities of ascorbic acid— as little as 6.5 mg daily—can result in a clinical cure.1,3 However, the dose that corrects the deficit and repletes body stores expeditiously is 100 mg thrice daily.3 Improvement can be dramatic, and sometimes within days, and usually within a few weeks. A subjective sense of wellbeing is often apparent within the first 24 hours, and the lethargy, pain, and anorexia diminish in two to three days. When joint symptoms occur, improvement is seen within a few days. The skin lesions become purplish, may become pigmented, and resolve eventually in a few weeks. Hyperkeratosis decreases in about two weeks. Except for lost teeth, permanent tooth damage from scurvy does not occur.3 Dietary advice is mandatory. More than 90% of vitamin C in western diets comes from fruits and vegetables, including potatoes, tomatoes, berries, green vegetables, and citrus fruits. Liver and kidney contain ample amounts, but most other meat, poultry, dairy products, and grain contain little or no ascorbic acid unless fortified.1,3 This patient’s symptoms, skin lesions, and muscle swelling improved dramatically with ascorbic acid repletion.
In summary, this patient had scurvy, alcoholic liver disease, and gallstones with extrahepatic biliary dilatation. He was advised to undergo endoscopic retrograde cholangiopancreatography as further work-up, but he refused and was discharged home.
Scurvy (hypovitaminosis C) with skin and soft tissue haemorrhage.