December 2003

4.

5.

Histopathology: A 4 mm punch biopsy obtained from the right back revealed multinodular aggregates of foam cells (lipid-rich macrophages) in the dermis (Fig. 4). These histiocytes stained positive for CD68 (Fig. 5) as well as vimentin. Smooth muscle actin and CD34 highlighted the vasculature only. These histopathological findings combined with the clinical presentation were consistent with xanthomata.

Diagnosis: Xanthomatosis secondary to primary biliary cirrhosis-related hyperlipidemia

Discussion:
Cutaneous xanthomas are characteristic of the hyperlipidemias (primary and secondary) which present with elevated levels of some or all of the plasma lipids (cholesterol, triglycerides, and phospholipids). Xanthomas represent the abnormal accumulation of lipids in skin macrophages (Fig. 4 and Fig. 5). They present clinically as yellow to yellow-brown or yellow-red papules, nodules, or plaques depending on their location and etiology.

The most common causes of xanthomata are the secondary forms of hyperlipidemia, including PBC. Other reported secondary causes of hyperlipidemia and xanthomata include drugs (estrogens, oral retinoids, thiazides, beta-blockers, alcohol), diabetes mellitus, hypothyroidism, pancreatitis, paraproteinemia, myeloma, and renal disease (i.e. nephrotic syndrome). Interestingly, one half of cases of isolated xanthelasma of the eyelids present with a normal lipid profile.

PBC is a chronic cholestatic liver disease thought to be autoimmune in origin (90% of patients present with anti-mitochondrial antibodies). PBC involves a progressive destruction of intrahepatic bile ducts with a high mortality rate if left untreated. Patients with PBC characteristically exhibit elevated plasma cholesterol and phopholipids with normal triglyceride levels. PBC can be associated with any type of xanthoma, however, plane xanthomas (Fig. 1 and Fig. 2) and tuberous xanthomas (Fig. 3) are a prominent feature of PBC. There may also be associated fatigue, pruritus, jaundice, and xanthomas of any type. Hyperpigmentation and pruritus associated with tuberous and planar xanthomas have been considered by some to be pathognomic for PBC.

The hypercholesterolemia in PBC is due to reduction in cholesterol secretion, and the treatment mainstay is liver transplantation. Although responses to systemic medications have been poor, ursodiol (Actigall) has been shown in some studies to increase survival, time to transplant, and reduce cholesterol levels. Other agents that may be helpful include azathioprine and cyclosporine. Unfortunately, none of these treatments have been shown to reliably improve xanthomatosis, and all patients will eventually require liver transplantation for survival.

References:

1. Leuschner U, et al. Primary biliary cirrhosis-presentation and diagnosis. Clinics in Liver Disease,Volume 7 · Number 4 · November 2003.
2. Hiroto Kita, PhD, MD et al. Pathogenesis of primary biliary cirrhosis. Clinics in Liver Disease,Volume 7 · Number 4 · November 2003.
3. Heathcote EJ. The clinical expression of primary biliary cirrhosis. Hepatology 2000, 31: 1005-1013.

My thanks to Drs. Shawn Allen and Jerri Hoskyn for assisting in the preparation of this case.