Volume 154, Issue 1 , Pages 116-118, January 2011
When nausea becomes a tricky question
Article Outline
Dear Editor,
In November 2008 we saw a 40-year-old primiparous woman, 27 weeks pregnant, in our emergency department, because of weakness and weight loss of 20
kg. She had had progressive nausea, vomiting and epigastric pain, with polyuria and polydipsia, since early pregnancy. Following several earlier medical consultations for these complaints she was treated for anemia. One day before admission the patient perceived reduced fetal movements. At presentation she was lethargic with low skin turgor. The fundus height corresponded to 27 weeks of pregnancy. Laboratory studies showed severe hypercalcemia (calcium 4.05mmol/l and albumin 27g/l) and increased parathyroid hormone-related protein (PTH-rp) concentration (PTH-rp 5.9 pmol/l, reference values 0–0.6pmol/l).
At this time, the fetus appeared viable, although a cardiotocogram showed little variation. Lung maturation was induced by betamethasone in case delivery was necessary. Meanwhile, plasma calcium lowering treatment with hyperhydration and diuretics appeared ineffective, so pamidronate was administered, which normalized maternal calcium levels. Two days later, the condition of the fetus worsened, making an emergency cesarean section necessary. A healthy baby girl with an Apgar score of 9 at 1 and 5min was born and admitted to the neonatal unit where hypercalcemia was diagnosed (calcium 4.27mmol/l and albumin 35g/l). The child's plasma calcium levels normalized with standard medical care, and she was swiftly transferred to the infant ward.
Once the girl was born, an abdominal CT scan was performed revealing a large lesion in the liver surrounded by multiple smaller lesions. A subsequent liver biopsy showed a poorly differentiated adenocarcinoma, probably primary intrahepatic cholangiocarcinoma based on immunohistochemistry (cytokeratin (CK)7 positive) and CK20, CEA, TTF-1, AFP, estrogen receptor negative with additional PTH-rp positive staining (Fig. 1).
Fig. 1.
H&E (A) and cytokeratin 7 (B) stains showing normal liver tissue (*) with transition to a poorly differentiated carcinoma (**) (magn. 200×). PAS-diastase stains revealed intracytoplasmic vacuolization (arrows), confirming an adenocarcinomatous differentiation (C); the tumor was positive (brown) for PTH-rp (D) (magn. 400×).
The patient's rapidly deteriorating condition precluded further therapy, and she died 3 months later at home. Her 21-month-old daughter is currently doing well and living with her father.
Nausea and vomiting are common symptoms related to pregnancy. However, in this patient these symptoms were the expression of severe hypercalemia by PTH-rp production related to thus far undetected cholangiocarcinoma. Co-existing symptoms like thirst, polyuria, fatigue, muscle weakness and lethargy had remained unrecognized. Increased production of PTH-rp as the cause of the humoral hypercalcemia of malignancy is frequently observed in patients with melanoma, lung, breast and renal cancers but PTH-rp may be secreted by virtually any type of tumor including cholangiocarcinoma [1]. In normal physiology PTH-rp levels are low, produced by various cell types [2]. PTH and PTH-rp have close homology and in part identical actions in elevating plasma calcium.
A physiologically small increase of PTH-rp as reported in pregnancy has been attributed to the production by both maternal and fetal tissues. However, this is rarely associated with increased maternal plasma calcium levels [3]. In general, total plasma calcium levels are lower in pregnant women due to hypoalbuminemia caused by dilution, with normal ionized calcium levels. Fetuses are able to regulate blood calcium levels irrespective of the maternal blood calcium level, but severe maternal hypercalcemia results in foetal hypercalcemia [4] and suppression of fetal parathyroid gland function. As a consequence, neonatal hypocalcemia can develop shortly after birth when maternal calcium flow is interrupted [5]. The patient's child had initially increased levels of calcium. However, an adequate fall in calcium levels resulted in normocalcemia, suggesting adequate PTH secretion.
The present case demonstrates that nausea and vomiting together with unexplained weight loss in a pregnant woman should always alert physicians to consider more unusual causes including rare entities such as undetected malignancy and hypercalcemia as a paraneoplastic syndrome.
Acknowledgements
We thank Danielle Meijer and Judith Bovee (Leiden University Medical Center) for help on PTH-rp staining.
References
- . Cholangiocellular carcinoma that produced both granulocyte-colony-stimulating factor and parathyroid hormone-related protein. Int J Clin Oncol. 2006;11(June (3)):246–249
- . Minireview: parathyroid hormone-related protein as an intracrine factor—trafficking mechanisms and functional consequences. Endocrinology. 2003;144(February (2)):407–411
- . Calcium and bone metabolism in pregnancy and lactation. J Clin Endocrinol Metab. 2001;86(June (6)):2344–2348
- . Maternal-fetal calcium and bone metabolism during pregnancy, puerperium, and lactation. Endocr Rev. 1997;18(December (6)):832–872
- . Primary hyperparathyroidism, pregnancy, and neonatal hypocalcemia. Surgery. 1984;96(4):717–722
PII: S0301-2115(10)00378-7
doi:10.1016/j.ejogrb.2010.07.044
© 2010 Elsevier Ireland Ltd. All rights reserved.
Volume 154, Issue 1 , Pages 116-118, January 2011
