Clinical-Pathological Conference Series from the Medical University of Graz

An ileocolonoscopy due to diarrhea 5 months prior to admission showed diffuse mucosal erythema of the descending and sigmoid colon. Biopsies showed nonspecific inflammation with slightly increased eosinophils in the lamina propria. Esophagogastroduodenoscopy with gastric and duodenal biopsies yielded normal results; the hydrogen breath test suggested lactose intolerance. His diarrhea resolved with a lactose-poor diet and 5‑aminosalicylic acid (5-ASA, 3 g per day for 3 months).

After an exacerbation of his psoriasis had persisted for 4 weeks he was admitted with pustules and progressive diffuse erythrodermia covering about 80 % of his body. The pustules were round with desquamating margins. On physical examination he was afebrile; his weight was 83 kg and height 178 cm. The finger- and toenails appeared normal. Several finger joints and the metacarpophalangeal (MCP) joints of both index and middle fingers were swollen and indurated without hyperthermia or erythema.

Routine laboratory tests, including a complete blood count, liver and renal function tests, erythrocyte sedimentation rate, C‑reactive protein (CRP) as well as antinuclear antibodies (ANA), anti-cyclic citrullinated peptide (anti-CCP) antibodies, immunoglobulin (Ig) G, IgA, IgM and anti-tissue-transglutaminase antibodies were normal or negative. Chest radiography and abdominal ultrasound were unremarkable. Plain radiographs of the hands showed irregular margins of the 2nd and 3rd MCP joints bilaterally with some small subchondral cysts and osteophytes on the radial side. Cystic changes were also seen in the carpal bones bilaterally, most pronounced in the os triquetrum and lunatum.

A diagnostic procedure was performed.

Focusing on the arthralgia of finger joints, it has to be emphasized that the 2nd and 3rd MCP joints on both hands were mainly affected. This is a very specific finding because osteoarthritis of the hand usually affects distal and proximal, interphalangeal and basal joints of the first ray, but not MCP joints. Further, the MCP joints of both index and middle fingers were described as swollen and indurated but without erythema and hyperthermia, which might be due to synovitis. Sonography of the hands would be helpful here and would allow differentiation between degenerative changes of the joints, psoriatic arthritis, perisynovitis, and other rheumatological diseases [4]. In addition to subchondral cysts and osteophytes, radiography also revealed irregular margins of the 2nd and 3rd MCP joints of both hands. These manifestations in the MCP joints are specifically found in Dietrich’s disease, an avascular necrosis. Causes for avascular necrosis include trauma (fracture or dislocation), caisson disease, hemoglobinopathies such as sickle cell disease, pregnancy, radiotherapy, connective tissue disorders, renal transplantation, corticosteroid excess (both endogenous and exogenous), pancreatitis, gout, Gaucher’s disease, and alcohol abuse [5]. However, since none of these causes seem to apply to our patient, I would exclude Dietrich’s disease as a differential diagnosis. Subchondral cysts as found here are typical for degenerative joint disease, rheumatoid arthritis, calcium pyrophosphate dihydrate (CPPD) crystal deposition disease, avascular necrosis, hemophilia, sickle cell disease, multiple myeloma, amyloidosis, hemochromatosis, Wilson’s disease, and hyperparathyroidism [6]. Since routine laboratory tests, including complete blood count, liver and renal function tests, erythrocyte sedimentation rate, CRP, ANA, anti-CCP antibodies, IgG, IgA, IgM, and anti-tissue-transglutaminase antibodies were normal or negative, most of those diseases can be excluded. However, the radiologic constellation with characteristic changes, subchondral cysts and osteophytes primarily affecting the 2nd and 3rd MCP joints of both hands is a typical finding in hemochromatosis. This is an iron metabolism disorder characterized by increased intestinal iron absorption and progressive deposition in organs and tissues resulting in injury and functional impairment, particularly in the liver, pancreas, heart, joints, and pituitary [7]. Laboratory findings include increased ferritin levels and enhanced transferrin saturation. Schumacher first recognized the relationship between hemochromatosis and arthritis in 1964 [8]. Joint pain is present in about 30 % of affected patients and is sometimes reported as the first symptom. Typically, the 2nd and 3rd MCP joints are involved but virtually any joint can be affected with signs and symptoms of osteoarthritis [9, 10]. Moreover, hook osteophytes along the radial aspect of the distal metacarpals are frequently found in arthropathy due to hemochromatosis. These hook osteophytes can also be seen in CPPD crystal deposition disease but are more prevalent in hemochromatosis. Generally, crystals are not associated with hemochromatosis arthropathy, but some patients may present with apatite and CPPD crystals, in which case arthritis mimics pseudogout (Table 1) [11, 12]. To further differentiate between hemochromatosis and CPPD crystal deposition disease, the following has to be considered: Both diseases involve the radiocarpal and midcarpal compartments of the wrist with diffuse joint space narrowing and intraarticular and periarticular calcifications, which are not seen with osteoarthritis. What helps to differentiate between hemochromatosis and CPPD crystal deposition disease is the joint space. In hemochromatosis arthropathy there is uniform loss of joint space at all the MCP joints including those of the ring and little fingers, while in CPPD crystal deposition disease there is narrowing predominantly of the index and the middle finger MCP joints [13]. Hook osteophytes may also be present on radiographs in cases of erosive arthropathy, but in erosive arthropathy distal interphalangeal joints are affected and clinically, these hook osteophytes have a distinct brown, wart-like appearance [14]. Since the pathological changes in this patient’s finger joints and his erythrodermia are not features of erosive arthropathy, this diagnosis can be ruled out.

Due to the clinical presentation, sarcoidosis or osteitis cystica multiplex (Jüngling’s disease), a slowly progressive form of osteitis with cystic changes extending into surrounding soft tissue in the acral regions (fingers, toes, nose) might also be considered as diagnosis here, if it were not for our patient’s normal chest radiographs.

Taken together, we have three important findings in this case: cystic arthropathy in the 2nd and 3rd MCP joints, pustulous psoriasis affecting 80 % of the skin, and eosinophilic colitis. The radiological findings strongly suggest arthropathy associated with hemochromatosis. Further laboratory data such as ferritin, transferrin saturation, and search for hemochromatosis gene mutations are needed to confirm this diagnosis. Moreover, I would suggest performing a skin biopsy to provide more information on his skin disease with pustulous psoriasis and erythrodermia.

Arthropathy due to hemochromatosis.

After our patient was diagnosed with hemochromatosis, therapeutic phlebotomy was initiated. Phlebotomy is the mainstay of treatment, both for initial depletion of excess iron stores and for subsequent maintenance of normal total body iron. There are no standardized guidelines but the efficacy of phlebotomy has been reported with an induction regime of removal of 500 ml of whole blood weekly (i. e. 200–250 mg iron) until the hematocrit falls 2–4 % below baseline and ferritin levels normalize to within 25–50 µg/l. Lifelong maintenance phlebotomy involves removal of 500 ml of whole blood every 2–4 months in men or every 3–12 months in women before menopause. This therapy usually allows maintenance of the serum ferritin level within the lower normal range. If iron parameters increase, suggesting inadequate iron removal, the frequency of phlebotomy has to be adapted. In the absence of contraindications, phlebotomized blood can be used for blood donation [20].

As mentioned, hemochromatosis is also associated with an enhanced risk for various infectious diseases because iron is an essential growth factor for many bacteria and increases bacterial virulence [32, 33]. Moreover, data indicate that iron has a significant unfavorable influence on the human gut microbiota and so may indirectly trigger intestinal inflammation in patients with hemochromatosis [32, 34]. This might have been a relevant contributing factor to our patient’s nonspecific colonic inflammation. We think that he had some form of infectious colitis that cleared. Recently, clinical observations highlight the relationship between iron and Helicobacter pylori infection. This infection is frequently associated with refractory iron deficiency anemia that responds favorably to Helicobacter pylori eradication [35, 36]. Helicobacter pylori can contribute to low iron status by different mechanisms. These include bacterial uptake of dietary and host-derived (lactoferrin, saturated transferrin, hemoglobin) iron, which increases virulence and may decrease human iron status. Increased virulence may accelerate development of atrophic gastritis, resulting in hypo- or achlorhydria and reduced secretion of vitamin C from the gastric epithelium, which also impairs iron uptake. Further, low iron status contributes to induction of gastric hepcidin, thus, promoting development of peptic ulcer [37, 38].

The influence of gastric acid secretion on iron absorption is also emphasized by the increased notion that achlorhydria in atrophic gastritis may be the sole cause of iron deficiency anemia [39, 40]. Therapeutic hypochlorhydria caused by proton pump inhibitors may thus reduce the frequency of phlebotomy in patients with hemochromatosis [41].

The liver biopsy showed mild enlargement of the portal fields with occasional porto-portal bridging, but no cirrhosis. There was mild necroinflammatory activity within the lobular parenchyma as well as mild steatosis. Iron stains showed marked accumulation of iron in hepatocytes and occasional macrophages within the portal fields (Fig. 2).

Hemochromatosis is an inherited disorder of iron metabolism leaving the patients unable to effectively regulate their iron absorption and so resulting in progressive accumulation of iron. Several different types of the disease have so far been described. In these individuals absorption of both inorganic and heme iron is increased [43] because basolateral efflux of iron from the enterocytes is inappropriately regulated [44, 45]; most importantly hepcidin levels are very low in patients with hemochromatosis type 1 (mutation of the HFE gene, MIM #235200) [46]. In a normal individual an increase in body iron levels would lead to increased hepcidin expression and this in turn would decrease iron absorption by reducing basolateral efflux. Such an increase in hepcidin does not occur in patients with HFE-associated hemochromatosis, so that their iron absorption continues in the face of body iron overload. Mutations of HFE, hemojuvenil, hepcidin, transferrin receptor 2 (TfR2), Ireg1, transferrin, ceruloplasmin and ferritin all lead to some form of iron overload [47]. Of these, mutations in the HFE gene located on chromosome 6 are by far the most common [48] and >80 % of patients with hemochromatosis are homozygous for HFE mutation C282Y (rs1800562, G845A) [49, 50]. HFE-associated hemochromatosis, the most common type in adults, is regarded as the most prevalent autosomally inherited genetic disease of Caucasians with an allele frequency of C282Y of 6.2 % and a homozygosity frequency of 0.38 % in a pool of 127,613 individuals. However, there is considerable variation across Europe with allele frequencies of >10 % in Ireland and 0–3 % in Mediterranean regions [27]. In the US, homozygosity for the C282Y mutation accounts for most cases of hemochromatosis followed by H63D and S65C mutations. Heterozygosity of C282Y and H63D is seen only infrequently. Penetrance of C282Y is, however, low. A population-based study revealed mildly elevated liver enzymes or liver disease in <10 % of C282Y homozygotes and the estimated prevalence of clinical hemochromatosis was as low as 1 % [51]. Other studies reported liver disease in up to 16 % of C282Y homozygotes [52]. In addition to the particular genetic variant, penetrance of the mutation and environmental factors such as diet, alcohol consumption, coexisting chronic viral hepatitis, and host factors such as gender, age, and obesity may influence the course of hemochromatosis-associated fibrosis and cirrhosis [27, 53]. Patients with HFE-associated hemochromatosis absorb excessive amounts of iron from birth, which entails excessive iron accumulation in parenchymal cells of the liver, heart, and endocrine organs [53]. While a normal adult male may have 3.5 g of storage iron in his body, patients with hemochromatosis may reach 20–30 g or more before clinical symptoms occur [18]. In my experience patients typically first present around age 50 due to hepatic symptoms; about 1/3 of affected patients have joint manifestations and are first seen by rheumatologists. Sometimes chondrocalcinosis and subsequent profound joint destruction of the knees, hips, or shoulders may have already necessitated joint replacement before the diagnosis of hemochromatosis. Hemochromatosis type 2, also defined as juvenile hemochromatosis, is divided into type 2A (mutation of the hemojuvenile gene, HJV, MIM #602390) and type 2B (mutation of the hepcidin antimicrobial peptide gene, HAMP, MIM #613313). Mutations in the transferrin receptor 2 (TFR2) gene were identified as a cause of hemochromatosis type 3 (MIM #604250) [54]. Hemochromatosis types 4 and 5 are associated with mutations of the ferroportin (Ireg 1) gene (SLC40A1, MIM #606069) and mutations of the H ferritin gene (FTH1, MIM #615517), respectively [55]. Genes associated with iron metabolism represent obvious candidates for mutations that lead to iron overload and disease phenotype in hemochromatosis. Further investigations will determine the role of each of these genes and their mutations and also of duodenal cytochrome b (DCYTB, CYBYRD1) and others in iron accumulation [47].

Hemochromatosis arthropathy.