Skin as a Mirror of Internal Disease

Review Article

SKIN AS A MIRROR OF INTERNAL DISEASE Murlidhar Rajagolalan Senior Consultant Dermatologist, Apollo Hospitals, 21, Greams Road, Off. Greams Road, Chennai 600 006, India. e-mail: [email protected] Key words: Skin mirror, Internal medicine

INTRODUCTION THE skin is the largest organ of the body. It is also an external organ. It has several functions, chief among which are immunological, metabolic, thermoregulation and of course, cosmetic. However, for the human body, the first three are very important for survival. This is because the skin has the same vasculature and immune system as the rest of the body; changes in the internal milieu of the body are hence readily reflected on the skin. The disposition of the skin as an external organ makes it an exciting and easily accessible organ to study many aspects of the body as a whole. The skin, therefore, has many external manifestations of rheumatic, immunologic, infectious and other systemic diseases including hematological; good study of the skin and a good dermatologist can help you to make not only an accurate assessment of the underlying disease, but also narrow down the precise management options for your patient. This brings into focus dermatology in internal medicine and the role of a dermatologist as an integrated specialist with an internal medicine team in a multispeciality team, delivering the best of care to the patient. This skill can be used to pick up an early diagnosis like an exanthema, diagnose a difficult vasculitis or narrow down the cause of a panniculitis. The dermatologist can also help you to manage a complication of a systemic drug used to treat an internal disease which has produced a drug reaction. Such reactions need to be recognized early and treated in an emergent manner. Fatal drug reactions present more often in the skin and are seen by the dermatologist first in order to arrive at a good management plan to save lives. 285

I will now proceed to illustrate this concept with examples and tables which is of help to internists PRURITUS Easily the commonest complaint in dermatology is itching. How many internists relate this to an internal, medical cause? If an external, dermatological cause like eczema or fungus is apparent, it is easy to call in the dermatologist and sort the problem. However, when the patient comes into the clinic with no apparent skin disease or with a multisystem internal disease which is being investigated, and pruritus is a major element, then the trouble starts! The patient more often than not, wants relief of the pruritus rather than give you the time to work up the internal disease. I have therefore listed below a workup which will be useful for internists when working up a patient with pruritus of unknown cause [1]. •

CBC count with differential: polycythemia vera, hematologic malignancies; iron deficiency However, those with pruritus and iron deficiency may not be anemic, tests of and serum iron, ferritin, and total iron-binding capacity may be ordered to confirm or exclude the diagnosis.

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Serum creatinine and blood urea nitrogen CRF.

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Serum alkaline phosphatase and bilirubin, direct and indirect: cholestasis. If elevated, antimitochondrial antibody and serum anti-hepatitis C tests may be ordered to confirm primary biliary cirrhosis and hepatitis C, respectively. Other tests may be needed to confirm other causes of cholestasis.

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Thyroid-stimulating hormone (TSH) and T4. Apollo Medicine, Vol. 3, No. 3, September 2006

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Fasting glucose symptoms

if

prompted

by

signs

or

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Stool for occult blood in patients aged 40 years or older: A positive result suggests possible malignancy in the GI tract.

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HIV antibody test if risk factors present.

Imaging studies

patients with renal failure have specific dermatologic signs which require elucidation. The problem one has to aware of is that renal patients may not tolerate many drugs which are normally used by physicians, hence dose modifications are required. This is where the dermatologist and internist or nephrologists learn to work together as team. To list a few of the specific diseases seen in chronic renal failure [2,3].

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Hodgkin disease, chest radiography.

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Acquired perforating disorder (Kyrle disease)

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If cholestasis is present, abdominal sonography.

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Xerosis Calcinosis cutis (metastatic)

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Half-and-half nails Uremic frost

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Alopecia Ischemic ulcerations

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Lichen simplex chronicus Pigmentary alteration

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Bullous disease of dialysis Calciphylaxis

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Nephrogenic sclerosing nephropathy Prurigo nodularis Xanthomas

Other tests •

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When results on initial laboratory screening are negative and when the physician still suspects a systemic cause Serum protein electrophoresis. •

Stool for ova and parasites.

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Urine for Hydroxy indole acetic acid (5HIAA) and mast cell metabolites.

Negative findings on initial evaluation do not necessarily exclude systemic disease, and follow-up screening may be repeated every 3-6 months if clinical suspicion continues.

PROCEDURES •

Endoscopic retrograde cholangiopancreatography (ERCP) should be performed when primary sclerosing cholangitis, choledocholithiasis, or obstructive malignancy is suspected.

•

Skin biopsy for direct immunofluorescence and special stains may help in ruling out a primary dermatologic condition, such as dermatitis herpetiformis or bullous pemphigoid (i.e., pruritic pemphigoid), or in confirming a systemic cause, such as in mastocytosis. Clues supporting a systemic cause include the insidious onset of generalized pruritus rather than an acute presentation

DERMATOLOGIC DISEASES ASSOCIATED WITH RENAL FAILURE This is by far the commonest cause for referral to a dermatologist working in a hospital like Apollo hospitals. Many patients with advanced renal disease have pruritus as discussed above. Many Apollo Medicine, Vol. 3, No. 3, September 2006

This is in order of occurrence. Some of the rare diseases have not been mentioned. One must remember that even when the urea levels have come back to normal after dialysis, the patient may continue to itch, most patients stop itching only after transplant. Hemodialysis itself can induce itching, even though the patient may be normouremic. One disease which we see but miss frequently in the renal wards is scabies. This can be notoriously difficult to pick up as the excoriations can be confounding. Some patients may present with Norwegian scabies and need prolonged therapy, even with short courses of methotrexate. Therapy of uremic pruritus is difficult. Most antihistamines fail to act. Ondansetron, naltrexone, phototherapy and regular use of emollients are approaches that are useful. One must always make a search for a specific cause before labeling it as purely uremic pruritus. Metabolic causes, especially related to parathyroid have to be ruled out. Patients with renal failure and secondary hyperparathyroidism can be particularly difficult to treat. Some may require parathyroidectomy [4-6].

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PRIMARY SYSTEMIC AMYLOIDOSIS While on the subject of metabolic diseases, it is interesting to see how a dermatologist can come to a diagnosis in a difficult systemic disease. One such metabolic disease is amyloidosis. Systemic amyloidosis can be classified: (i) primary systemic amyloidosis (PSA), usually with no evidence of preceding or coexisting disease, paraproteinemia, or plasma-cell dyscrasia; (ii) amyloidosis associated with multiple myeloma; or (iii) secondary systemic amyloidosis with evidence of coexisting previous chronic inflammatory or infectious conditions. One such patient presented for a general check up this is his history. CASE STUDY He was a middle aged man with a history of progressive weakness over the last three years and no other specific symptom on presentation. On elucidation during workup, he had fatigue, weight loss, hoarseness, parasthesias and some tingling of the digits. He had mild hepatomegaly and peripheral edema. He sought dermatologic help as he was unable to close his mouth due to an unusually large tongue! The diagnosis was made from a tongue biopsy. We know that abdominal fat and rectal biopsy can also be done to confirm the diagnosis of amyloidosis. He turned out to have advanced renal involvement and thus a poor prognosis. A Dermatologist can pick up. Some of them are: Clinically evident mucocutaneous involvement occurs in 30-40% of patients with PSA, and it provides an early clue to the existence of an underlying plasma-cell dyscrasia. Petechiae and ecchymoses are the most common skin findings, because of cutaneous blood vessel involvement. The face is most commonly affected; minor trauma sometimes precipitates eyelid and periorbital purpura (pinch purpura). Purpuric lesions are found in flexural regions such as the nasolabial folds, neck, and axillae.

that may be evident in the eyelids, retro auricular region, neck, or inguinal and anogenital regions [7-9]. PARANEOPLASTIC SKIN SIGNS Several times the dermatologist may point you to the existence of an underlying malignancy in the patient [10]. The most famous or rather infamous of the lot is the ‘sign of leser trélat’. It refers to the sudden eruption of multiple seborrhoiec keratosis caused by a malignancy. Many cases in the literature are poorly documented. Its linkage with malignant acanthosis nigricans is one of a number of its features that support its classification as a true paraneoplastic syndrome. The sign of Leser-Trélat is usually associated with an adenocarcinoma, often in the stomach and the colon. Other rarely associated paraneoplastic entities include the following: • Acquired hypertrichosis lanuginosa • Acquired ichthyosis • Cowden disease • Tylosis • Acrokeratosis of Bazex • Tripe palms [11,12] ERYTHRODERMA While on the subject of paraneoplastic syndromes, it is worthwhile to consider erythroderma. Most internists would have seen erythroderma rather than these rare paraneoplastic syndromes. Erythroderma refers to the diffuse redness associated with thickening and scaling affecting at 80% of the human body. This is usually an end stage of several skin diseases, but this can also be the presentation of internal disease. The skin disease may be as simple as psoriasis or even eczema, but especially in the elderly, one should consider that this may be a marker of an internal malignancy.

At times, hemorrhagic bullae form. The most characteristic skin lesion in PSA consists of waxy papules, nodules, or plaques 287

The common cancers which result in erythroderma are lymphomas, prostate cancers and GI malignancies. Apollo Medicine, Vol. 3, No. 3, September 2006

Review Article

ACANTHOSIS NIGRICANS

Pancreatic fat necrosis

This refers to the thick blackish pigmentation seen on the folds and sometimes on the hands or even other parts of the body.

Pancreatic fat necrosis describes the association of skin nodules with pancreatic disease. These nodules may be painless to begin with, but become painful soon thereafter. They represent a panniculitis or inflammation of the subcutaneous fat and subsequent digestion of the fat by pancreatic proteases. Two-third of patients with pancreatic cancer present with this symptom.

Acanthosis occurs due to the stimulation of the skin by growth factors, these may be insulin like growth factors–when this occurs and the patient is obese or has insulin resistance, the patient is at risk for NIDDM. Alternately, the source for the growth factor may also be genetic or may be rarely paraneoplastic. The paraneoplastic Acanthosis Nigricans is called tripe palms, a distinctive entity in itself which warrants a diligent search for malignancy, esp. pertaining to the gut. Acanthosis Nigricans in a young adult should prompt the search for insulin resistance and the metabolic syndrome

This is a small vessel vasculitis that involves the post capillary venules. There is a deposition of IgA in these venules and palpable purpura is the major symptom, though sometimes, there may be cuta-neous necrosis too. The major GI symptom here is acute abdominal pain, which may be the presenting symptom; this is due in most cases due to mild bowel ischemia due to vasculitis involving the bowel [13-16]. COMMON DRUG REACTIONS AND HOW TO RECOGNISE THEM

Dermatologic manifestations of gastrointestinal disease We have seen several skin signs of gastrointestinal disease so far. There area few more which deserve special mention as they are distinctive and interesting–both for the reader and the physician! Scleroderma (systemic sclerosis) This is a multisystem disorder in which there is prominent systemic involvement of the skin, lungs, heart and kidney. The primary pathology in that of diffuse fibrosis and vasculopathy leading to decrease in blood supply to vital organs, this can also result in gastrointestinal disease, especially dysmotility, severe reflux due to a lax g-e junction and at times even present to the emergency with bowel necrosis. Sister Mary Joseph nodule Sister Mary Joseph was the first to note that the presence of a periumbilical nodule heralded an advanced intra-abdominal malignancy. The cutaneous finding is a firm, nontender nodule of red or purple hue that represents a metastasis from the primary tumor. 90% of these malignancies are adenocarcinoma, with gastric and ovarian being the most common. Apollo Medicine, Vol. 3, No. 3, September 2006

Henoch-Schönlein purpura

The internist’s nightmare is the adverse drug reaction. Practically any drug can react adversely in a given patient, as most reactions are idiosyncratic. One of the commonest reaction is the fixed drug reaction–this occurs most commonly with metronidazole or sulphas, and is manifest by a grayish patch, reddish to begin with that recurs at the same site every time the drug is given. In most cases this is benign and only a nuisance. The severe reactions constitute the Stevens Johnson reactions, the toxic epidermal necrolysis reactions and the severe erythema multiforme type of reactions. In these reactions, there is widespread desquamation of the skin and mucous membranes, more in TEN than in SJS, with pronounced systemic toxicity due to sepsis, metabolic compromise and coagulation disorders. Leucopenia, tachycardia are bad prognosticators here. Apart from supportive therapy and treatment of complications on a day to day basis aggressively, there is no agreement yet on the optimum management of these reactions. Steroids may worsen the morbidity if given for too long–how much is not defined. Of late Intravenous immunoglobulin and cyclosporine have found a role in managing these drug reactions. Considering their innate toxicity, they have to be administered cautiously.

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SKIN SIGNS OF CONNECTIVE TISSUE DISORDERS

3. Urbonas A, Schwartz RA, Szepietowski JC. Uremic pruritus–an update. Am J Nephrol 2001; 21(5): 343350.

No discussion will be complete without a few words on this–easily the most common area where there is overlap of two specialties is rheumatology and dermatology.

4. Mettang T, Pauli-Magnus C, Alscher DM. Uraemic pruritus–new perspectives and insights from recent trials. Nephrol Dial Transplant 2002; 17(9): 1558-1563. 5. Massry SG, Popovtzer MM, Coburn JW, et al. Intractable pruritus as a manifestation of secondary hyperparathyroidism in uremia. Disappearance of itching after subtotal parathyroidectomy. N Engl J Med 1968; 279(13): 697-700.

The famous signs of SLE are only too well known for me to go into here–the malar rash, the oral ulcers, the discoid rash and hair loss. Photosensitivity is prominent. There are many others which one can write about, but that will be beyond the scope of a simple review like this.

6. Schwartz IF, Iaina A. Management of uremic pruritus. Semin Dial 2000; 13(3): 177-180. 7. Breathnach SM. Amyloid and amyloidosis. J Am Acad Dermatol 1988; 18(1 Pt 1): 1-16.

Scleroderma has been touched upon earlier–but this disease has specific skin signs–sclerotic skin, proximal scleroderma, sclerodactyly, prominent nail fold capillaries and salt and pepper pigmentation to name a few. Dermatomyositis presents with photosensitivity, a peculiar purplish rash on the eyelids called the heliotrope sign and papules on the fingers called gottrons papules. CONCLUSION To conclude, I have just given a few examples of how dermatology can be of help to an internist in arriving at an accurate diagnosis. The list of skin signs in internal medicine will cover at least one textbook as of date. I have tried to give a few examples different systems which can demonstrate the link between the skin and the internal milieu. Subsequently we can expand on this and see the details of each system in the body and how to become better internists by just recognizing skin signs alone. REFERENCES 1. Ständer S, Steinhoff M, Schmelz M, et al. Neurophysiology of pruritus: Cutaneous elicitation of itch. Arch Dermatol 2003; 139(11): 1463-1470. 2. Carmichael AJ. Renal itch. In: Itch: Mechanisms and Management of Pruritus. 1994: 217-228.

8. Xavier SD, Bussoloti IF, Muller H. Macroglossia secondary to systemic amyloidosis: case report and literature review. Ear Nose Throat J 2005; 84(6): 358361. 9. Falk RH, Comenzo RL, Skinner M. The systemic amyloidoses. N Engl J Med 1997; 337(13): 898-909. 10. Kebria MM, Belinson J, Kim R, Mekhail TM. Malignant acanthosis nigricans, tripe palms and the sign of Leser-Trélat, a hint to the diagnosis of early stage ovarian cancer: a case report and review of the literature. Gynecol Oncol 2006; 101(2): 353-355. 11. Stone SP, Buescher LS. Life-threatening paraneoplastic cutaneous syndromes. Clin Dermatol 2005; 23(3): 301306. 12. Fargnoli MC, Frascione P. Images in clinical medicine. Acanthosis nigricans. N Engl J Med 2005; 353(26): 2797. 13. Dahl PR, Su WP, Cullimore KC, Dicken CH. Pancreatic panniculitis. J Am Acad Dermatol 1995; 33(3): 413-417. 14. Gunasekaran TS. Henoch-Schonlein purpura: what does the “rash” look like in the gastrointestinal mucosa? Pediatr Dermatol 1997; 14(6): 437-440. 15. Longshore acanthosis carcinoma malignancy.

SJ, Taylor JS, Kennedy A. Malignant nigricans and endometrioid adenoof the parametrium: The search for J Am Acad Dermatol 2003; 49(3): 541-543.

16. Steen VD, Medsger TA Jr. Severe organ involvement in systemic sclerosis with diffuse scleroderma. Arthritis Rheum 2000; 43(11): 2437-2444.

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